CN102458374A - Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same - Google Patents

Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same Download PDF

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Publication number
CN102458374A
CN102458374A CN2010800304562A CN201080030456A CN102458374A CN 102458374 A CN102458374 A CN 102458374A CN 2010800304562 A CN2010800304562 A CN 2010800304562A CN 201080030456 A CN201080030456 A CN 201080030456A CN 102458374 A CN102458374 A CN 102458374A
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calcium phosphate
activating agent
phosphate granules
granule
agent
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CN2010800304562A
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扎赫拉·曼苏里
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Laboratory Skin Protection Ltd Co
Laboratory Skin Care Inc
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Laboratory Skin Protection Ltd Co
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Application filed by Laboratory Skin Protection Ltd Co filed Critical Laboratory Skin Protection Ltd Co
Priority to CN201910174558.4A priority Critical patent/CN110075069A/en
Publication of CN102458374A publication Critical patent/CN102458374A/en
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Abstract

Dermal delivery compositions are provided. Aspects of the dermal delivery compositions include the presence of active agent-calcium phosphate particle complexes, where these complexes include uniform, rigid, spherical nanoporous calcium phosphate particles associated with one or more active agents. Also provided are methods of using the compositions in active agent delivery applications.

Description

The dermal delivery compoistion and method of use that comprises activating agent-calcium phosphate granules complex
The cross reference of related application
According to 35U.S.C. § 119 (e), the serial number that the application requires on May 6th, 2009 to submit to is the priority that 61/176,057 U.S. Provisional Patent Application is submitted to day; The content of this application is incorporated this paper by reference into.
Background technology
And holding the multiple different activity agent of exploitation comprises disease and non-disease symptoms to be used to treating multiple different symptom with continuing.For this application, must give the experimenter who needs with the bioactive agent delivery of effective dose.Developed multiple different delivery formulation and route of delivery, wherein this approach can change according to the character of activating agent to some extent.Generally, Wicresoft's route of delivery is better approved, is better therefore.
The one type of route of delivery that receives very big concern is a dermal delivery, because it has the traumatic of minimum.In dermal delivery, surfactant composition is applied to skin part, thereby gives the experimenter bioactive agent delivery.That use or that be in evaluation stage at present many dermal delivery technology are not entirely satisfactory.For example, some dermal delivery technology can be destroyed the integrity of horny layer (Sc) and/or depend on the existence of penetration enhancer, and penetration enhancer can cause damage and/or the stimulation of not expecting.In addition, some dermal delivery technology possibly be based on the technology of polymer and/or liposome, and these two kinds of technology all do not have to send via Sc veritably.In addition, these technology can not be applied to macromolecule bioactive substance etc.
Thus, still need develop new dermal delivery technology to overcome one or more shortcomings that present dermal delivery method is had.
Summary of the invention
The dermal delivery compositions is provided.The aspect of said dermal delivery compositions comprises and has activating agent-calcium phosphate granules complex that wherein these complex comprise and the spherical nanoporous calcium phosphate granules of the bonded even rigidity of one or more activating agents.Also be provided at activating agent and send the said method for compositions of use in the application.
Description of drawings
Figure 1A to 2B provides the scanning electron microscope image of the spherical nanoporous calcium phosphate granules of even rigidity that can be applicable in the delivering compositions of the present invention.
Fig. 3 provides the diagram of the particle size distribution of the spherical nanoporous calcium phosphate granules of even rigidity that can be applicable in the delivering compositions of the present invention.
Fig. 4 shows the visual pattern of the activating agent that is attached to calcium phosphate granules.
Fig. 5 A and 5B show forearm are used the tape stripping image behind the 10% calcium phosphate granules slurry.Fig. 5 A shows that calcium phosphate granules is penetrated into cuticular ground floor.Fig. 5 B shows that calcium phosphate granules is penetrated into cuticular the 3rd layer.
Fig. 6 is the mouse skin image before the application of phosphoric acid calcium granule.There is not tangible Ca in the epicuticle ++
Fig. 7 A show in the epicuticle the calcium granule and down in the horny layer than granule.Fig. 7 B shows the particulate integrity loss of spherical calcium.
Fig. 8 is the photo of the infiltration of CTC fluorescent material in the middle of whole horny layer after the demonstration local application.
Fig. 9 shows the result carry out the STAY-C50 when not carrying out the calcium phosphate granules tape stripping.
The form of Figure 10 shows through what tape stripping was measured and has and the number and percentage that does not have the lysozyme of calcium phosphate granules.
Figure 11 shows and has and the Franz cell transdermal delivery that does not have single lactofiavine phosphate activating agent of calcium phosphate granules.
The specific embodiment
The present invention provides the dermal delivery compositions.The aspect of said dermal delivery compositions comprises and has activating agent-calcium phosphate granules complex that wherein these complex comprise and the spherical nanoporous calcium phosphate granules of the bonded even rigidity of one or more activating agents.Also be provided at activating agent and send the said method for compositions of use in the application.
This specific embodiments before further describing the present invention, it being understood that the present invention is not limited to described specific embodiments, because can change.What it is also understood that is, the purpose of term used herein only is in order to describe concrete embodiment, but not is intended to have the meaning of restriction, because scope of the present invention is only limited appended claims.
When numerical range is provided; Should be understood that; Each intermediate value between the upper and lower limit of this scope (except that context has clear and definite regulation in addition, calculate lower limit unit 1/10th) and any value that other is mentioned or intermediate value in this said scope include within the present invention.These upper and lower limits more among a small circle can be included in independently this more among a small circle in, and be also included within the present invention, do not include any limit value of clearly getting rid of in the middle of the said scope.When said scope comprised one or two limit value, any one or both scopes got rid of in these included limit values were also included among the present invention.
Some scope that provides among this paper has term " about " in the numerical value front.Term " about " be used in this article to thereafter definite numeral and near or the numeral that is similar to the numeral of this term back the literal support is provided.A definite numeral whether near or when being similar to specifically enumerate digital, near or proximate do not enumerate numeral in the context of its appearance can be equal to basically specifically enumerate digital numeral.
Can implement cited method among this paper by any feasible in logic order of cited incident and cited event sequence.
Except that other had definition, all scientific and technical terminologies used herein all had the implication identical with those skilled in the art's common sense.Though in enforcement of the present invention or test, also can use and any method and material similar described in this paper or that be equal to, will describe preferable methods and material now.
All publications of mentioning among this paper are all incorporated this paper by reference into, with open method and/or the material relevant with the publication of quoting with description.It only is to the disclosure before the application's submission day that publication discussed herein is provided.Any foregoing among this paper all should not be interpreted as owing to the former of invention formerly thereby admit that the present invention has no reason early than this type of publication.In addition, the publication date that is provided possibly be different from the actual publication date, and the actual publication date possibly confirmed independently.
Must be noted that except that context has clearly regulation in addition, be used in singulative " ", " " in this paper and the appended claims and reach " said " and comprise the plural thing that refers to.Be pointed out that further claim can be formulated as and not comprise any optional key element.In this connection, this statement is intended to as use basic in advance such as exclusiveness term such as " only ", " only " or employing " negative " restriction with regard to the statement of claim key element.
In further describing each side of the present invention; Activating agent-calcium phosphate granules according to some embodiment has been described in more detail; The embodiment of the delivering compositions that comprises said activating agent-calcium phosphate granules has been described then, and preparation and use said complex and comprise the method for the delivering compositions of said complex.
Delivering compositions
Such as preceding text general introduction, provide activating agent to send compositions.Activating agent of the present invention is sent compositions and is comprised the activating agent-calcium phosphate granules complex that is present in the delivery vector.Independent in more detail now activating agent-calcium phosphate granules complex delivery vector component of discussing delivering compositions.
Activating agent-calcium phosphate granules complex
Activating agent-calcium phosphate granules the complex that is present in the delivering compositions of the present invention comprises and the spherical nanoporous calcium phosphate granules of the bonded even rigidity of one or more activating agents.When granule combined with one or more activating agents, one or more activating agents were incorporated into said granule with certain mode.Activating agent can be incorporated into said granule via many different combining forms, and these forms include but not limited to: ionic bonding, covalent bonding, Van der Waals interaction, interaction of hydrogen bond, positive and anti-phase distribute interaction etc.Thus, can said granule be described as load a certain amount of one or more activating agents are arranged." load " is meant that granule comprises a certain amount of one or more activating agents (in other words, a certain amount of single-activity agent or two kinds or more kinds of different activity agent), and said activating agent is incorporated into said granule.Because activating agent is incorporated into said granule, so when said granule was present in the middle of the delivering compositions, activating agent can not dissociate from granule with any significant amount.Because there is not activating agent from granule, to dissociate out basically, so by the weight of the initial binding capacity of activating agent, any certain dissociated amount is 30% or still less, as 20% or still less, for example be 10% or still less, comprise 5% or still less.The amount that is incorporated into particulate active agent component (being made up of one or more different activity agent) can be different; This depends on that forming activating agent combines particulate concrete activating agent situation; This is measured and is 0.01mg/g to 1000mg/g in certain embodiments; Like 0.1mg/g to 750mg/g, comprise 1mg/g to 300mg/g activating agent/gram granule.
Activating agent combines with calcium phosphate granules reversiblely." combine reversiblely " to be meant after sending, for example, skin site used after the delivering compositions that comprises said complex that activating agent is discharged from calcium phosphate granules to the experimenter.Discuss in more detail like hereinafter, the calcium phosphate granules of complex is 5 or littler at pH value for example under acid condition, for example pH value be 4.9 or littler, pH value be 4.7 littler, pH value be 4.5 or littler, pH value be 4.3 or littler condition under degrade.When granule was degraded, they discharged its activating agent " payload (payload) ".Horny layer (SC) is the outermost layer of skin, is made up of the about 10 μ m of thickness about 20 confluent monolayer cells.The pH value of SC is looked its degree of depth and is different.Its outermost pH value from 4.3 to 7.0 does not wait, and this depends on the position or the individual sex of sampling.This pH value is brought up to about 7.0 near granulosa (SG).As follows, this raising is last the most remarkable in which floor the SC's that presses close to SG.Thus, along with complex of the present invention infiltrates SC, they can be degraded and discharge with it bonded any activating agent simultaneously.
Although the activating agent that discharges once with complex in calcium phosphate granules combine, also kept its required activity.Therefore, activating agent is with the combination of calcium phosphate granules and discharge the destruction very little basically (if any) that activating agent is produced.Thus; The activity of activating agent is not reduced to the degree that influences its effectiveness unfriendly; Wherein for example measure (for example hereinafter experimental section described in) by activity determination method; Be reduced to 10% or littler by the caused any activity of the contingent combination of given activating agent,, comprise 1% or littler as 5% or littler with calcium phosphate granules.
In some embodiments, one or more favourable characteristics that combine to have kept activating agent of activating agent and calcium phosphate granules in the complex are like stability.In other words, compare with the contrast that does not have calcium phosphate granules, complex makes the activating agent stabilisation.
The spherical nanoporous calcium phosphate granules of even rigidity
The calcium phosphate granules of activating agent-calcium phosphate granules complex is the spherical nanoporous calcium phosphate granules of even rigidity." evenly " is meant that coating of particles is constant basically, thereby granule has substantially the same spherical form." rigidity " is meant that granule is very hard, thereby they are not flexible.Term " sphere " is used for representing circle on conventional meaning, have a few basically and the center equidistance on its surface.The median particle diameter of the calcium phosphate granules of being paid close attention to is 20 μ m or littler, like 10 μ m or littler, comprises 5 μ m or littler, and wherein in some cases, median particle diameter is 4 μ m or littler, like 3 μ m or littler, comprises 2 μ m or littler.In given calcium phosphate granules compositions, can there be particle size distribution; Wherein in some cases; Great majority (as 60% or more, 75% or more, 90% or more, 95% or more) particulate diameter range at 0.01 μ m to 20 μ m; Like 0.1 μ m to 10 μ m, comprise 0.1 μ m to 2 μ m.In some cases, mean diameter is that 2 μ m or littler proportion of particles count 50% or more by number, as 70% or more, comprises 90% or more.
Said granule is a nanoporous." nanoporous " is meant that particulate porosity is 30% or bigger; As 40% or bigger; Comprise 50% or bigger; Wherein press described in the ASTM D 4284-88 " Standard Test Method for Determining Pore Volume Distribution of Catalysts by Mercury Intrusion Porosimetry ", adopt mercury injection apparatus (mercury intrusion porosimeter) porosity measurement scheme to measure, the scope of porosity can be 30% to 85%; As 40% to 70%, comprise 45% to 55%.Also describe porosity through " pore volume (ml/g) ", many in this case is 0.1ml/g to 2.0ml/g.In some cases, granule has such porosity, makes that its internal surface area scope was 10m when employing was measured by the BET gas absorption surface area test scheme described in ASTM D3663-03 catalyst and the catalyst carrier surface area standard testing method 2/ g to 150m 2/ g is like 20m 2/ g to 100m 2/ g comprises 30m 2/ g to 80m 2/ g.The aperture can be different, and its scope like 5nm to 80nm, comprises 10nm to 60nm at 2nm to 100nm in some cases.In addition, particulate tap density scope can be 0.2g/cm 3To 0.5g/cm 3, like 0.25g/cm 3To 0.45g/cm 3, comprise 0.3g/cm 3To 0.4g/cm 3The measurement of tap density can adopt standard A STM WK13023-to measure the new method of the tap density of metal dust through the constant volume measuring method.
In some cases, granule is chemical pure.Chemical pure is meant that granule is made up of one type calcium phosphate mineral basically.In some cases, calcium phosphate granules is by molecular formula Ca 10(PO 4) 6(OH) 2Describe.
In some cases, granule is a ceramic particle.Pottery is meant that employing comprises what the method for the step that makes granule stand hot conditions was produced, and wherein this condition is as follows.Pyritous scope can be 200 ℃ to 1000 ℃, as 300 ℃ to 900 ℃, comprises 300 ℃ to 800 ℃.In some embodiments; Particulate compressive failure strength range is at 20MPa to 200MPa; Like 50MPa to 150MPa, comprise 75MPa to 90MPa, this is to adopt MCT-W500 minute-pressure test machine granule strength measurement scheme that contracts in Tianjin, island to measure; The sintering of granule under 400 ℃ to 900 ℃ temperature is described in European patent EP 1840661.
In some embodiments, said granule is biodegradable, this be meant granule under physiological condition As time goes on and with certain mode (for example, dissolving) degraded.Because the granule of these embodiments is biodegradable under physiological condition, so they are 5 or lower at pH value, as 4.5 or lower, comprise 4.3 or lower condition under begin dissolving with detectable speed at least.Thus, granule pH value be 5 or lower sour environment under, when for example being applied to skin, demonstrate dissolubility.
Calcium phosphate granules is nontoxic (for example, confirming through US-FDA 21 CFR Part 58), non-mutagenic (for example, confirming through the test of mutagenicity Ames) and nonirritating (for example, definite through skin sensitivity RIPT (mankind)).
Though the various different parameters (comprising as stated) of the spherical nanoporous calcium phosphate granules of even rigidity of delivering compositions can change; But in some embodiments, employed granule is the chemical pure granule with 2 μ m average diameters in the delivering compositions.
Can adopt any suitable scheme to prepare the spherical nanoporous calcium phosphate granules of even rigidity of delivering compositions of the present invention.The example of the fabrication scheme of being paid close attention to includes but not limited to United States Patent (USP) 4,781,904,5,039,408,5,082,566 and 5,158, and those described in 756, foregoing are incorporated this paper by reference into.In a scheme of being paid close attention to, said particulate manufacture is, spray drying comprises that the slurry of nano-calcium phosphate (for example, hydroxyapatite) crystal (said crystal can in the scope of 2nm to 100nm) is to produce even spheric nanoporous calcium phosphate granules.With resulting granules sintering a period of time, the said time is enough to obtain machinery and chemically stable rigid ball then.In this step, sintering temperature can be 200 ℃ to 1000 ℃, as 300 ℃ to 900 ℃, comprises 300 ℃ to 800 ℃, and sintering time is 1 hour to 10 hours, as 2 hours to 8 hours, comprises 3 hours to 6 hours.Serial number is the more details that the manufacturing approach of the spherical nanoporous calcium phosphate granules of relevant evenly rigidity is provided in 61/108,805 the U.S. Provisional Application, and the content of this application is incorporated this paper by reference into.
Activating agent
Like preceding text general introductions, complex of the present invention comprises the active agent component that is incorporated into the spherical nanoporous calcium phosphate granules of even rigidity (being processed by the activating agent of single type or two kinds or more kinds of dissimilar activating agent).Term " activating agent " be meant with live organism, mammal for example produces physiologic effect, for example useful or the chemical compound of useful effect or the mixture of chemical compound when contacting like the people.Activating agent can be different from other component of delivering compositions, like carrier, diluent, lubricant, binding agent, coloring agent etc.Activating agent can be any molecule that can regulate the biological process among the experimenter alive with and bound fraction or segment.In certain embodiments, activating agent can be used to diagnose, treatment or prevent disease or as the material of the component of medicine, cosmetics or cosmeceutical.
Activating agent be with the experimenter that lives in target interact or influence or the live chemical compound of the target among the experimenter of adjustment otherwise.Said target can be many dissimilar natural structures, and the target of wherein being paid close attention to comprises target and extracellular target in the cell.Activating agent can comprise one or more functional groups, and said functional group provides and be scheduled to the structural interaction of target.The functional group that is paid close attention to includes but not limited to: the group of participating in hydrogen bond, hydrophobic-hydrophobic interaction, electrostatic interaction.The concrete group of being paid close attention to includes but not limited to amine, amide, sulfydryl, carbonyl, hydroxyl, carboxyl etc.
The activating agent of being paid close attention to can comprise with the substituted ring carbon of one or more above-mentioned functional groups or heterocycle structure and/or fragrance or poly aromatic structure.As what the part of activating agent was also paid close attention to the structure in the middle of the biomolecule of being shown in arranged, comprise peptide, saccharide, fatty acid, steroid, purine, pyrimidine, their derivant, analog or combination.Can screen this chemical compound with identification paid close attention to those, wherein various screening scheme is as known in the art.
Activating agent can be derived from natural or synthetic chemical compound, and said natural or synthetic compound can derive from source widely, comprises synthetic or native compound storehouse.For example, many methods can be used for reaching at random the organic compound and the biomolecule of directed synthetic broad variety, comprise preparation randomization oligonucleotide and oligopeptide.Perhaps, the native compound storehouse of antibacterial, fungus, plant and animal extracts form is available or be easy to produce.In addition, chemistry, physics and biochemical method that storehouse natural or that produce with synthesis mode and chemical compound are easy to through routine carry out modification, and can be used for producing combinatorial libraries.Can carry out orientation or chemical modification at random to known pharmacological reagent, like acidylate, alkanisation, esterification, amidatioon etc., to produce analog.
Thus, activating agent can derive from natural or the synthetic molecules storehouse, comprises the compound library that produces through combined method, i.e. chemical compound multiformity combinatorial libraries.When deriving from this storehouse, employed activating agent will demonstrate some ideal activity in suitable screening active ingredients analysis.The method in combinatorial libraries and generation and this storehouse of screening is as known in the art, and in following patent, describes to some extent: 5,741,713,5,734,018,5,731,423,5,721,099,5; 708,153,5,698,673,5,688,997,5,688,696,5,684,711,5; 641,862,5,639,603,5,593,853,5,574,656,5,571,698,5; 565,324,5,549,974,5,545,568,5,541,061,5,525,735,5; 463,564,5,440,016,5,438,119,5,223,409, above-mentioned patent content is incorporated this paper by reference into.
The activating agent of being paid close attention to comprises little, medium and the macromole activating agent.The small molecule active agent be molecular weight ranges 18 to 2500 dalton, like 1000 to 1500 dalton, comprise 250 to 1000 daltonian activating agents.The medium molecule activating agent be molecular weight ranges 2500 to 10,000 dalton, like 4,000 to 8,000 dalton, comprise 5000 to 7000 daltonian activating agents.The macromole activating agent is that molecular weight is 10,000 dalton or bigger, as 100; 000 dalton or bigger activating agent; Wherein the scope of these macromole activating agents like 500 ten thousand to 2,000 ten thousand dalton, comprises 1,000 ten thousand to 1,000 5 megadaltons 100 ten thousand to 3,000 ten thousand dalton in some cases.
In certain embodiments, activating agent exists with the form of its salt, so that the electric charge that they carry allows them to be incorporated into the spherical nanoporous calcium phosphate granules of even rigidity of delivering compositions in a desired manner.
The activating agent of being paid close attention to includes but not limited to that serial number is a listed activating agent in the appendix A of 61/176,057 U. S. application; The content of above-mentioned application is incorporated this paper by reference into.
The activating agent of the broad variety of being paid close attention to includes but not limited to: cardiovascular drugs; Pain relief agents, for example analgesic, anesthetis, anti-inflammatory agent etc.; The effects on neural system agent; Chemotherapy (for example antitumor) agent; Or the like.The activating agent of being paid close attention to includes but not limited to:
Antibiotic; As: aminoglycoside, for example amikacin (amikacin), apramycin (apramycin), arbekacin (arbekacin), bambermycin (bambermycins), butirosin (butirosin), dibekacin (dibekacin), dihydrostreptomycin (dihydrostreptomycin), fortimicins (fortimicin), gentamycin (gentamicin), isepamicin (isepamicin), kanamycin (kaniamycin), micronomicin (micronomcin), neomycin (neomycin), netilmicin (netilmicin), paromomycin (paromycin), ribostamycin (ribostamycin), sisomicin (sisomicin), spectinomycin (spectinomycin), streptomycin (streptomycin), tobramycin (tobramycin), trospectomycin (trospectomycin); Amide alcohols (amphenicols), for example azidamfenicol (azidamfenicol), chloromycetin (chloramphenicol), florfenicol (florfenicol) and the non-Buddhist nun of Saimaa can (theimaphenicol); Ansamycins (ansamycins), for example rifamide (rifamide), rifampicin (rifampin), rifamycin (rifamycin), rifapentine (rifapentine), rifaximin (rifaximin)); The b-lactams, for example carbacephems (carbacephems), carbapenems (carbapenems), cephalosporins (cephalosporins), cephamycin-type (cehpamycins), monobactam class (monobactams), oxacephems (oxaphems), PCs; Lincosamide class (lincosamides), for example that mycin of crin (clinamycin), lincomycin (lincomycin); Macrolide, for example clarithromycin (clarithromycin), reason mycin (dirthromycin), erythromycin (erythromycin) etc.; Polypeptide class, for example Dermokalixan (amphomycin), bacitracin (bacitracin), capreomycin (capreomycin) etc.; Tetracyclines, for example apicycline (apicycline), duomycin (chlortetracycline), clomocycline (clomocycline), minocycline (minocycline) etc.; Synthetic antibacterial agents, as 2,4-diaminopyrimidine, itrofurans, quinolones and analog thereof, sulfonamides, sulfone class;
Antifungal; As: polyenoid class, for example amphotericin B, cannitracin (candicidin), Dermastatin. (dermostatin), filipin (filipin), fungichromin (fungichromin), hachimycin (hachimycin), hamycin (hamycin), lucensomycin (lucensomycin), mepartricin (mepartricin), natamycin (natamycin), nystatin (nystatin), pecilocin (pecilocin), Aminomycin (perimycin); Synthetic antifungal drug, like propylamine, for example butenafine (butenafine), naftifine (naftifine), terbinafine (terbinafine); Imidazoles, for example bifonazole (bifonazole), butoconazole (butoconazole), clodantoin (chlordantoin), chlormidazole (chlormidazole) etc.; Thiocarbamates for example asks former times to draw ester (tolcilate); Triazole type, for example fluconazol (fluconazole), itraconazole (itraconazole), terconazole (triaconazole) (terconazole));
Anthelmintic, as: arecoline (arecoline), pannol (aspidin), 4-butyryl-2-methylphloroglucinol 1-methyl ether (aspidinol), dichlorophen (dichlorophen), grace shellfish plain (embelin), toil (kosin), naphthalene, niclosamide (niclosamide), pelletierine (pelletierine), quinacrine (quinacrine), constuslactone (alantolactone), amocarzine (amocarzine), amoscanate (amoscanate), ascaridole (ascaridole), bepheninum (bephenium), bitoscanate (bitoscanate), carbon tetrachloride, carvacrol (carvacrol), ciclobendazole (cyclobendazole), diethylcarbamazine (diethylcarbamazine) etc.;
Antimalarial, as: acedapsone (acedapsone), amodiaquine (amodiaquin), arteether (arteether), Artemether (artemether), arteannuin (artemisinin), artesunate (artesunate), atovaquone (atovaquone), bebeerine (bebeerine), berberine (berberine), Herba Swertiae bimaculatae (chirata), proguanil, chloroquine, chlorproguanil (chlorproguanil), Cortex Cinchonae (cinchona), cinchonidine (cinchonidine), cinchonine (cinchonine), cyclochloroguanidum (cycloguanil), gentiopicrin (gentiopicrin), Halofantrine (halofantrine), hydroxychloroquine, Mefloquine Hydrochloride (mefloquine hydrochloride), 3-methylarsacetin (3-methylarsacetin), pamaquine (pamaquine), antimalarine (plasmocid), first quinoline (primaquine), pyrimethamine (pyrimethamine), quinacrine (quinacrine), Kui Buddhist nun's pyridine (quinidine), quinine, quinocide (quinocide), quinoline, disodium hydrogen arsenate;
Antiprotozoal, as: An Kelani (acranil), tinidazole (tinidazole), ipronidazole (ipronidazole), ethylstibamine (ethylstibamine), pentamidine (pentamidine), acetarsol (acetarsone), acinitrazole (aminitrozole), Fructus Anisi Stellati mycin (anisomycin), nifuratel (nifuratel), tinidazole (tinidazole), benzene Rieter azoles (benzidazole), suramin (suramin);
The spirit pharmacological prepn; Like (1) central nervous system depressant; For example general anesthetis (group of barbiturates, Benzodiazepines, steroid, cyclohexanone derivative and assorted agent), sedative hypnotic (Benzodiazepines, group of barbiturates, piperidine dione class and three ketones, quinazoline derivant, carbamates, aldehydes and derivant, amide-type, acyclic ureide derivative, tall and erect type of benzo nitrogen and related drugs, phenothiazines etc.), central voluntary muscle tension force improvement medicine (anticonvulsant; Like hydantoins (hydantoins), group of barbiturates 、 oxazolidinedione class, butanimide class, acyl group ureide derivative (acylureides), ring valeryl imines class, Benzodiazepines, secondary alcohol and the tertiary alcohol, dibenzazepine derivative, valproic acid and derivant, GABA analog etc.), analgesic (morphine and derivant, O3-demethylthebaine. derivant, morphinan derivative, phenylpiperidine, 2; 6-methane-3-anaesthesine derivant, diphenylprop amine and same part, salicylic acid salt, p-aminophenyl amphyl, 5-pyrazolone derivative, Arylacetic acids derivant, fragrant that Barbiturates (fenamates) and with part etc.) and Bendectin (anticholinergic agent, antihistaminic, anti-dopamine medicine etc.); (2) central nervous system stimulant; For example analeptic (respiratory stimulant, convulsions analeptic, psychomotor stimulant), narcotic antagonist (morphine derivatives, O3-demethylthebaine. derivant, 2; 6 methane-3-anaesthesine derivant, morphinan derivative), nootropics; (3) psychopharmacologica1 agent; For example anxiety tranquilizer (Benzodiazepines, propylene glycol carbamates) psychosis (phenothiazine derivative, Thioxanthine derivatives, other tricyclic compound, phenyl propyl ketone derivant and same part, diphenyl butylamine derivant, substituted benzamides, aryl piperazine derivative, indole derivatives etc.), antidepressants (tricyclic compounds, MAO inhibitor etc.); (4) respiratory drugs, for example central antitussive (Opium alkaloids and derivant thereof);
The drug effect agent; Like (1) peripheral nervous system medicine; Local anesthetic (ester derivant, amide derivatives) for example; (2) act on the medicine of synapse or neural effector link position; For example cholinergic agents, cholinergic blocking agent, neuromuscular blocking agents, adrenergic agent, antiadrenergic agent; (3) smooth muscle active medicine; For example separate contraction medicine (anticholinergic, separate the contraction medicine), vasodilation, smooth muscle stimulant, (4) histamine and antihistaminic, for example histamine and derivant thereof (ametazole (betazole)), antihistaminic (H1-antagonist, H2-antagonist), histamine metabolism drug thing to muscle property; (5) cardiovascular drugs; For example cardiac tonic (plant extract, butenolide class (butenolides), pentadienoic acid lactone (pentadienolids), alkaloids, ionophore ,-adrenergic receptor stimulant etc.), anti-arrhythmic, antihypertensive, antilipemic agent (clofibric acid (clofibric acid) derivant, nicotinic acid derivant, hormone and analog, antibiotic, salicylic acid and derivant), antivaricose drug, hemorrhage from the Erythrophleum kind, (6) blood and hemopoietic system medicine, for example anti-anemic drug, coagulant (hemorrhage, anticoagulant, antithrombotic agents, thrombolytics, haemproteins and part thereof) (7) gastrointestinal drug; For example digestive pharmaceutical (stomachic, choleretic), antiulcerative, diarrhea, (8) local action medicine;
Chemotherapeutics; Like (1) anti-infective; For example ectoparasiticide (chlorinated hydrocarbons, cinerins, sulfuration chemical compound), anthelmintic, antiprotozoan agent, anti-malarial agents, anti-ameba agent, antileishmanial, anti-trichomonal agent, antitrypanosomal agent (antitrypanosomal), sulfonamides, mycobacteria agent medicine, antiviral chemotherapeutics etc.; (2) cytostatics; Be antitumor agent or cytotoxic drugs; Like alkylating agent, for example mustine hydrochlcride (Mechlorethamine hydrochloride) (chlormethine, mechlorethamine (Mustargen), HN2), cyclophosphamide (Cytovan, Endoxana), ifosfamide (ifosfamide) are (IFEX), chlorambucil (Chlorambucil) (Chlorambucil (Leukeran)), melphalan (Melphalan) (phenylalanine mustard, L-Sarcolysin (sarcolysin), L-Sarcolysinum (Alkeran), L-PAM), busulfan (Busulfan) (bridle blue (Myleran)), plug be for send (Thiotepa) (three stretch ethyl plug replace send (Triethylenethiophosphoramide)), carmustine (Carmustine) ((BiCNU, BCNU), lomustine (Lomustine) (CeeNU, CCNU), streptozocin (Streptozocin) (streptozotocin (Zanosar)) etc.; Vegetable alkaloids, for example vincristine (vinblastin (Oncovin)), vinblastine (vincaleucoblastine (Velban), vinblastine sulfate (Velbe)), taxol (Paclitaxel) (paclitaxel (Taxol)) etc.; Antimetabolite; For example methotrexate (Methotrexate) (MTX), mercaptopurine (purine mercaptan (Purinethol, 6-MP), thioguanine (6-TG), fluorouracil (5-FU), cytosine arabinoside (Cytosar-U, Ara-C), azacitidine (Azacitidine) (Mylosar, 5-AZA) etc.; Antibiotic; For example dactinomycin (actinomycin D, Cosmegen), amycin (Doxorubicin) (adriamycin (Adriamycin)), daunomycin (Daunorubicin) (duanomycin; Cerubidine), IDA (Idarubicin) (darubicin (Idamycin)), bleomycin A5 (Bleomycin) (Bleomycin Sulphate (Blenoxane)), plicamycin (Picamycin) (mithramycin (Mithramycin), mithramycin (Mithracin)), mitomycin (Mitomycin) (mutamycin (Mutamycin)) etc.; And other cellular antiproliferative agent; For example hydroxyurea (hydroxyl urea (Hydrea)), procarbazine (Procarbazine) (Mutalane), dacarbazine (Dacarbazine) (DTIC-Dome), cisplatin (Cisplatin) (cisplatin (Platinol)) carboplatin (Carboplatin) (Paraplatin (Paraplatin)), asparaginase (leunase (Elspar)) etoposide (VePesid; VP-16-213, peace kill gram peaceful (Amsarcrine) (AMSA, m-AMSA), mitotane (Mitotane) (Lysodren), mitoxantrone (Mitoxantrone) (Novatrone) etc.
The medical compounds of being paid close attention to is also listed in the following document: Goodman & Gilman ' s, The Pharmacological Basis of Therapeutics (the 9th edition) (people such as Goodman edits) (McGraw-Hill) (1996); With 2001 Physician ' s Desk Reference.
The concrete kind and the example of activating agent include but not limited to: be shown in the activating agent in the following table:
Figure BPA00001496795600141
Figure BPA00001496795600151
Figure BPA00001496795600161
Figure BPA00001496795600171
Figure BPA00001496795600191
The particular compound of being paid close attention to also includes but not limited to:
Figure BPA00001496795600201
Figure BPA00001496795600211
Figure BPA00001496795600221
Figure BPA00001496795600231
Figure BPA00001496795600241
The particular compound of being paid close attention to also includes but not limited to:
Antineoplastic agent is as disclosed in the following United States Patent (USP): 5880161,5877206,5786344,5760041,5753668,5698529,5684004,5665715,5654484,5624924,5618813,5610292,5597831,5530026,5525633,5525606,5512678,5508277,5463181,5409893,5358952,5318965,5223503,5214068,5196424,5109024,5106996,5101072,5077404,5071848,5066493,5019390,4996229,4996206,4970318,4968800,4962114,4927828,4892887,4889859,4886790,4882334,4882333,4871746,4863955,4849563,4845216,4833145,4824955,4785085,476925,4684747,4618685,4611066,4550187,4550186,4544501,4541956,4532327,4490540,4399283,4391982,4383994,4294763,4283394,4246411,4214089,4150231,4147798,4056673,4029661,4012448;
Spirit pharmacology/psychiatric department medicine is as disclosed in the following United States Patent (USP): 5192799,5036070,4778800,4753951,4590180,4690930,4645773,4427694,4424202,4440781,5686482,5478828,5461062,5387593,5387586,5256664,5192799,5120733,5036070,4977167,4904663,4788188,4778800,4753951,4690930,4645773,4631285,4617314,4613600,4590180,4560684,4548938,4529727,4459306,4443451,4440781,4427694,4424202,4397853,4358451,4324787,4314081,4313896,4294828,4277476,4267328,4264499,4231930,4194009,4188388,4148796,4128717,4062858,4031226,4020072,4018895,4018779,4013672,3994898,3968125,3939152,3928356,3880834,3668210;
Cardiovascular drugs is as disclosed in the following United States Patent (USP): 4966967,5661129,5552411,5332737,5389675,5198449,5079247,4966967,4874760,4954526,5051423,4888335,4853391,4906634,4775757,4727072,4542160,4522949,4524151,4525479,4474804,4520026,4520026,5869478,5859239,5837702,5807889,5731322,5726171,5723457,5705523,5696111,5691332,5679672,5661129,5654294,5646276,5637586,5631251,5612370,5612323,5574037,5563170,5552411,5552397,5547966,5482925,5457118,5414017,5414013,5401758,5393771,5362902,5332737,5310731,5260444,5223516,5217958,5208245,5202330,5198449,5189036,5185362,5140031,5128349,5116861,5079247,5070099,5061813,5055466,5051423,5036065,5026712,5011931,5006542,4981843,4977144,4971984,4966967,4959383,4954526,4952692,4939137,4906634,4889866,4888335,4883872,4883811,4847379,4835157,4824831,4780538,4775757,4774239,4771047,4769371,4767756,4762837,4753946,4752616,4749715,4738978,4735962,4734426,4734425,4734424,4730052,4727072,4721796,4707550,4704382,4703120,4681970,4681882,4670560,4670453,4668787,4663337,4663336,4661506,4656267,4656185,4654357,4654356,4654355,4654335,4652578,4652576,4650874,4650797,4649139,4647585,4647573,4647565,4647561,4645836,4639461,4638012,4638011,4632931,4631283,4628095,4626548,4614825,4611007,4611006,4611005,4609671,4608386,4607049,4607048,4595692,4593042,4593029,4591603,4588743,4588742,4588741,4582854,4575512,4568762,4560698,4556739,4556675,4555571,4555570,4555523,4550120,4542160,4542157,4542156,4542155,4542151,4537981,4537904,4536514,4536513,4533673,4526901,4526900,4525479,4524151,4522949,4521539,4520026,4517188,4482562,4474804,4474803,4472411,4466979,4463015,4456617,4456616,4456615,4418076,4416896,4252815,4220594,4190587,4177280,4164586,4151297,4145443,4143054,4123550,4083968,4076834,4064259,4064258,4064257,4058620,4001421,3993639,3991057,3982010,3980652,3968117,3959296,3951950,3933834,3925369,3923818,3898210,3897442,3897441,3886157,3883540,3873715,3867383,3873715,3867383,3691216,3624126;
Antimicrobial is as disclosed in the following United States Patent (USP): 5902594,5874476,5874436,5859027,5856320,5854242,5811091,5786350,5783177,5773469,5762919,5753715,5741526,5709870,5707990,5696117,5684042,5683709,5656591,5643971,5643950,5610196,5608056,5604262,5595742,5576341,5554373,5541233,5534546,5534508,5514715,5508417,5464832,5428073,5428016,5424396,5399553,5391544,5385902,5359066,5356803,5354862,5346913,5302592,5288693,5266567,5254685,5252745,5209930,5196441,5190961,5175160,5157051,5096700,5093342,5089251,5073570,5061702,5037809,5036077,5010109,4970226,4916156,4888434,4870093,4855318,4784991,4746504,4686221,4599228,4552882,4492700,4489098,4489085,4487776,4479953,4477448,4474807,4470994,4370484,4337199,4311709,4308283,4304910,4260634,4233311,4215131,4166122,4141981,4130664,4089977,4089900,4069341,4055655,4049665,4044139,4002775,3991201,3966968,3954868,3936393,3917476,3915889,3867548,3865748,3867548,3865748,3783160,3764676,3764677;
Anti-inflammatory drugs, such as disclosed in the following U.S. patents: the 5872109,5837735,5827837,5821250,5814648,5780026,5776946,5760002,5750543,5741798,5739279,5733939,5723481,5716967,5688949,5686488,5686471,5686434,5684204 , 5684041,5684031,5684002,5677318,5674891,5672620 5665752,5656661,5635516,5631283,5622948,5618835,5607959,5593980,5593960,5580888,5552424,5552422 5516764,5510361,5508026,5500417,5498405,5494927 , 5476876,5472973,5470885,5470842,5464856,5464849,5462952,5459151,5451686,5444043,5436265,5432181, RE034918, 5393756,5380738,5376670,5360811,5354768,5348957,5347029,5340815,5338753,5324648,5319099,5318971 , 5312821,5302597,5298633,5298522,5298498,5290800,5290788,5284949,5280045,5270319,5266562,5256680,5250700,5250552,5248682,5244917,5240929,5234939,5234937,5232939,5225571,5225418,5220025,5212189,5212172 , 5208250,5204365,5202350,5196431,5191084,5187175,5185326,5183906,5177079,5171864,5169963,5155122,5143929,5143928,5143927,5124455,5124347,5114958,5112846,5104656,5098613,5095037,5095019,5086064,5081261 , 5081147,5081126,5075330,5066668,5059602,5043457,5037835,5037811,5036088,5013850,5013751,5013736,500654,4992448,4992447,4988733,4988728,4981865,4962119,4959378,4954519,4945099,4942236,4931457,4927835 , 4912248,4910192,4904786,4904685,4904674,4904671,4897397,4895953,4891370,4870210,4859686,4857644,4853392,4851412,4847303,4847290,4845242,4835166,4826990,4803216,4801598,4791129,4788205,4778818,4775679 , 4772703,4767776,4764525,4760051,4748153,4725616,4721712,4713393,4708966,4695571,4686235,4686224,4680298,4678802,4652564,4644005,4632923,4629793,4614741,4599360,4596828,4595694,4595686,4594357,4585755 , 4579866,4578390,4569942,4567201,4563476,4559348,4558067,4556672,4556669,4539326,4537903,4536503,4518608,4514415,4512990,4501755,4495197,4493839,4465687,4440779,4440763,4435420,4412995,4400534,4355034 , 4335141,4322420,4275064,4244963,4235908,4234593,4226887,4201778,4181720,4173650,4173634,4145444,4128664,4125612,4124726,4124707,4117135,4027031,4024284,4021553,4021550,4018923,4012527,4011326,3998970 , 3998954,3993763,3991212,3984405,3978227,3978219,3978202,3975543,3968224,3959368,3949082,3949081,3947475,3936450,3934018,3930005,3857955,3856962,3821377,3821401,3789121,3789123,3726978,3694471,3691214 , 3678169,3624216;
Immunosuppressant is as disclosed in the following United States Patent (USP): 4450159,4450159,5905085,5883119,5880280,5877184,5874594,5843452,5817672,5817661,5817660,5801193,5776974,5763478,5739169,5723466,5719176,5696156,5695753,5693648,5693645,5691346,5686469,5686424,5679705,5679640,5670504,5665774,5665772,5648376,5639455,5633277,5624930,5622970,5605903,5604229,5574041,5565560,5550233,5545734,5540931,5532248,5527820,5516797,5514688,5512687,5506233,5506228,5494895,5484788,5470857,5464615,5432183,5431896,5385918,5349061,5344925,5330993,5308837,5290783,5290772,5284877,5284840,5273979,5262533,5260300,5252732,5250678,5247076,5244896,5238689,5219884,5208241,5208228,5202332,5192773,5189042,5169851,5162334,5151413,5149701,5147877,5143918,5138051,5093338,5091389,5068323,5068247,5064835,5061728,5055290,4981792,4810692,4410696,4346096,4342769,4317825,4256766,4180588,4000275,3759921;
Analgesic is as disclosed in the following United States Patent (USP): 5292736,5688825,5554789,5455230,5292736,5298522,5216165,5438064,5204365,5017578,4906655,4906655,4994450,4749792,4980365,4794110,4670541,4737493,4622326,4536512,4719231,4533671,4552866,4539312,4569942,4681879,4511724,4556672,4721712,4474806,4595686,4440779,4434175,4608374,4395402,4400534,4374139,4361583,4252816,4251530,5874459,5688825,5554789,5455230,5438064,5298522,5216165,5204365,5030639,5017578,5008264,4994450,4980365,4906655,4847290,4844907,4794110,4791129,4774256,4749792,4737493,4721712,4719231,4681879,4670541,4667039,4658037,4634708,4623648,4622326,4608374,4595686,4594188,4569942,4556672,4552866,4539312,4536512,4533671,4511724,4440779,4434175,4400534,4395402,4391827,4374139,4361583,4322420,4306097,4252816,4251530,4244955,4232018,4209520,41645144147872,4133819,4124713,4117012,4064272,4022836,3966944;
Cholinergic agents is as disclosed in the following United States Patent (USP): 5219872,5219873,5073560,5073560,5346911,5424301,5073560,5219872,4900748,4786648,4798841,4782071,4710508,5482938,5464842,5378723,5346911,5318978,5219873,5219872,5084281,5073560,5002955,4988710,4900748,4798841,4786648,4782071,4745123,4710508;
Adrenergic agent is as disclosed in the following United States Patent (USP): 5091528,5091528,4835157,5708015,5594027,5580892,5576332,5510376,5482961,5334601,5202347,5135926,5116867,5091528,5017618,4835157,4829086,4579867,4568679,4469690,4395559,4381309,4363808,4343800,4329289,4314943,4311708,4304721,4296117,4285873,4281189,4278608,4247710,4145550,4145425,4139535,4082843,4011321,4001421,3982010,3940407,3852468,3832470;
Hydryllin is as disclosed in the following United States Patent (USP): 5874479,5863938,5856364,5770612,5702688,5674912,5663208,5658957,5652274,5648380,5646190,5641814,5633285,5614561,5602183,4923892,4782058,4393210,4180583,3965257,3946022,3931197;
Alclometasone diproionate is as disclosed in the following United States Patent (USP): 5863538,5855907,5855866,5780592,5776427,5651987,5346887,5256408,5252319,5209926,4996335,4927807,4910192,4710495,4049805,4004005,3670079,3608076,5892028,5888995,5883087,5880115,5869475,5866558,5861390,5861388,5854235,5837698,5834452,5830886,5792758,5792757,5763361,5744462,5741787,5741786,5733899,5731345,5723638,5721226,5712264,5712263,5710144,5707984,5705494,5700793,5698720,5698545,5696106,5677293,5674861,5661141,5656621,5646136,5637691,5616574,5614514,5604215,5604213,5599807,5585482,5565588,5563259,5563131,5561124,5556845,5547949,5536714,5527806,5506354,5506221,5494907,5491136,5478956,5426179,5422262,5391776,5382661,5380841,5380840,5380839,5373095,5371078,5352809,5344827,5344826,5338837,5336686,5292906,5292878,5281587,5272140,5244886,5236912,5232915,5219879,5218109,5215972,5212166,5206415,5194602,5166201,5166055,5126488,5116829,5108996,5099037,5096892,5093502,5086047,5084450,5082835,5081114,5053404,5041433,5041432,5034548,5032586,5026882,4996335,4975537,4970205,4954446,4950428,4946834,4937237,4921846,4920099,4910226,4900725,4892867,4888336,4885280,4882322,4882319,4882315,4874855,4868167,4865767,4861875,4861765,4861763,4847014,4774236,4753932,4711856,4710495,4701450,4701449,4689410,4680290,4670551,4664850,4659516,4647410,4634695,4634693,4588530,4567000,4560557,4558041,4552871,4552868,4541956,4519946,4515787,4512986,4502989,4495102; Above-mentioned disclosure is incorporated this paper by reference into.
The analog of being paid close attention to that also has above-claimed cpd.For all above-mentioned activating agents, activating agent can exist with pharmaceutically acceptable salt class form, as stated.
The delivery vector component
Delivering compositions of the present invention is to be mixed with the compositions that is used for bioactive agent delivery is delivered to local location, said local location such as mammalian subject such as people experimenter's keratinized skin surface or mucomembranous surface.Cornified skin surface is meant experimenter's skin site, i.e. the outside coating of animal body or the position of crust.Mucomembranous surface is meant experimenter's the position that comprises mucosa, like inboard, oral cavity, intranasal side etc.
Because dermal delivery preparation of the present invention is to be mixed with for delivery to local location, so it is compatible that they are mixed with and prepare the local location physiology that they are directed against.Therefore, when contacting with preparation target angle materialization skin surface that they were directed against or mucomembranous surface, delivering compositions (if any) basically can not cause the physiological reaction (like inflammation or stimulation) that makes delivering compositions not be suitable for local application.
Delivering compositions of the present invention comprises a certain amount of activating agent-calcium phosphate granules complex, and said activating agent-calcium phosphate granules complex is included in the delivery vector component.The delivery vector component is meant in the delivering compositions it is not that part of of activating agent-calcium phosphate granules complex component.
The delivery vector component of delivering compositions of the present invention can change as required, and the concrete composition of wherein given delivery vector component depends on the character of concrete compositions at least in part.The delivering compositions of being paid close attention to comprises: liquid preparation, like lotion (contain the liquid of insoluble matter with suspension or emulsion form, intend and be used for external application, comprise the spraying lotion) and aqueous solution; Semi-solid preparation is like gel (wherein decentralized photo merged with disperse medium and produce the colloid of semi-solid material such as jelly), cream (soft solid or thick liquid) and ointment (soft, ointment formulation); And solid preparation, like topical plaster.Thus, the delivery vector component of being paid close attention to includes but not limited to: oil-in-water (O/W) and Water-In-Oil (W/O) type emulsion, emulsion formulation, lotion, cream, ointment, gel, serosity, powder, facial film, dressing, spray, aerosol or patch.
Lotion
Lotion is a fluid composition; Viscosity is 50 when wherein using rotary viscosity measuring; 000cP or littler; As 10,000cP or littler, said rotating cylinder viscometer is measured viscosity through the running moment of torsion that measurement is immersed in the cylindrical rotor in the sample; The viscosimetric analysis scheme is implemented under 25 ℃ temperature, described in JIS K 7117:Testing Methods For Viscosity With A Rotational Viscometer Of Resins In The Liquid or ASTM D 2196-86:Test Methods for Rheological Properties on Non-Newtonian Materials by Rotational (Brookfield) Viscometer.
The lotion delivery vector component of being paid close attention to can comprise many different compositions, includes but not limited to: water, softening agent, natural oils, silicone oil, thickening agent or viscosity modifier, synthetic or Natural ester, fatty acid, alcohols, wetting agent, emulsifying agent, preservative system, coloring agent, spice etc.As required, these amount of substances can as 0.1% to 50%, comprise 1% to 20% for 0.001% to 99% of composition weight.
Softening agent is to substitute lipid and the natural oils in the skin or make an addition to lipid and the chemical compound of natural oils in the skin.Intend with in this article term softening agent and to comprise conventional lipid matter (for example, fat, wax and other water-insoluble materials), polar lipid (for example, be modified and make it have more water miscible lipid matter), siloxanes and hydrocarbon.The softening agent of being paid close attention to includes but not limited to: diisopropyl adipate, isopropyl myristate, isopropyl palmitate, ethylhexyl palmitate, Dermol 105, benzoic acid C 12-15Alcohol ester, di-ethylhexyl maleate, PPG-14 butyl ether, PPG-2 myristyl ether propionic ester, ricinoleic acid cetyl, cholesterol ester stearic acid, cholesterol isostearate, cholesterol acetate, Jojoba oil, cocoa butter, Adeps Bovis seu Bubali seeds of trees oil, lanoline and lanoline ester.
Silicone oil can be divided into volatility kind and non-volatile kind.Term " volatility " with in this article is meant the material that has measurable vapour pressure at ambient temperature.The volatile silicone oils of being paid close attention to includes but not limited to: the ring-type or the straight chain polydimethylsiloxane that contain 4 to 5 silicon atoms of 3 to 9 silicon atoms.Straight chain volatile siloxane material can have 5 centistokes or littler viscosity down at 25 ℃, and annular material can have 10 centistokes or littler viscosity.The non-volatile silicone oil of being paid close attention to includes but not limited to: gather alkylsiloxane, polyoxyethylene alkyl aryl radical siloxane and polyether siloxane copolymer.The nonvolatile basically alkylsiloxane of being paid close attention to that gathers comprises the polydimethylsiloxane that is 5 to 100,000 centistokes 25 ℃ of following viscosity for example.
Suitable ester includes but not limited to: have the thiazolinyl or the Arrcostab of the fatty acid of 10 to 20 carbon atoms, like isopropyl palmitate, isostearic acid isopropyl ester, isononyl isononanoate, myristic acid oleyl alcohol ester, stearic acid oleyl alcohol ester and Cetiol; The ether-ester class is like the fatty acid ester of ethoxylized fatty alcohol; Polyol ester; Ethylene glycol fatty acid ester and ethylene glycol bisthioglycolate fatty acid ester; Diethylene glycol mono fatty acid ester and diethylene glycol di fatty acid ester, Polyethylene Glycol (200-6000) mono fatty acid ester and Polyethylene Glycol (200-6000) di fatty acid ester; Propylene glycol mono fatty acid ester and propylene glycol di fatty acid ester are like polypropylene glycol 2000 monoleates, polypropylene glycol 2000 monostearates, ethoxylated propylene glycol monostearate; Mono fatty acid glyceride and difatty acid glyceride; Polyglycereol polyglycerol fatty acid ester is like ethoxylation glyceryl monostearate, 1,3 butylene glycol monostearate, 1,3 butylene glycol distearate; The polyoxyethylene polyols fatty acid ester; Sorbitan carboxylic esters; And polyoxyethylene sorbitan carboxylic ester, they are gratifying polyol esters; The wax ester class is like Cera Flava, spermaceti, myristyl myristate, stearic acid stearyl ester; Sterol esters, its example has Generol 122 and cholesterol fatty acid ester.Can use these chemical compounds plant and animal origin both.The example of this oil includes but not limited to: Oleum Ricini, lanolin oil, C10-18 triglyceride, caprylic/capric triglyceride, Semen pruni armeniacae oil, almond oil, sesame seed oil, Caulis et Folium Lini shepherd's purse seed oil, fine jade precipice Caulis et folium euphorbiae milii (tamanu) seed oil, Semen Maydis oil, Oleum Gossypii semen, Semen Lini oil, China ink oil, olive oil, Petiolus Trachycarpi oil, Borneo (illipe) fat, Oleum Brassicae campestris, soybean oil, Oleum Vitis viniferae, Oleum Helianthi, Semen Juglandis wet goods.Also suitable have synthetic or semisynthetic glyceride, as the fatty acid list-, two-and triglyceride, its natural fat or oils for being modified, for example the list of polyhydric alcohol (like glycerol)-, two-or three esters.In an example, make fat (C12-22) carboxylic acid and one or more multiple glyceryl reaction.Tristerin, two isostearic acids, two glyceride, polyglyceryl-3 isostearate, polyglyceryl-4 isostearate, polyglyceryl-6 ricinoleate, NOFABLE GO-902P, two glyceryl isostearates, four glyceryl isostearates, tricaprylin, distearyl acid two glyceride, linoleic acid glyceride, myristin, glyceryl isostearate, PEG Oleum Ricini, PEG olein, PEG tristerin and PEG tallow fatty acid glyceride.
The fatty acid of being paid close attention to includes but not limited to: have the fatty acid of 10 to 30 carbon atoms, like n-nonanoic acid, lauric acid, myristic acid, Palmic acid, stearic acid, isostearic acid, hydroxy stearic acid, oleic acid, linoleic acid, castor oil acid, arachidic acid, mountain Yu acid and erucic acid.
The wetting agent of polyhydric alcohol type also can be applicable in the compositions; Wherein the example of polyhydric alcohol includes but not limited to: glycerin (being also referred to as glycerol), gather alkane glycol, enediol and derivant thereof; Comprise propylene glycol, dipropylene glycol, polypropylene glycol, Polyethylene Glycol and derivant thereof, sorbitol, hydroxypropyl sorbitol, hexanediol, 1; 3-butanediol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and composition thereof.That also pays close attention to has a saccharide, for example, and glucose, fructose, Mel, hydrogenated honey, inositol, maltose, mannitol, maltose alcohol, sorbitol, sucrose, xylitol, xylose etc.When having wetting agent, the scope of its amount can be 0.001% to 25% by the weight of compositions, according to appointment 0.005% to 20%; Comprise about 0.1% to 15%; Wherein in some cases, the scope of the dosage of preserving moisture is 0.5% to 30%, as between 1% and 15%.
Emulsifying agent also can be present in the carrier compositions.When having emulsifying agent, by total composition weight meter, its total concentration scope can be 0.01% to 40%, as 1% to 20%, comprises 1% to 5%.The emulsifying agent of being paid close attention to comprises but is not limited to: anionic property, nonionic, cationic and amphiprotic activity material.The nonionic surfactant of being paid close attention to comprises that every mole of hydrophobe is had and about 2 C to about 100 moles of ethylene oxide or expoxy propane condensation 10-C 20The surfactant of aliphatic alcohol or sour hydrophobe; C with 2 to 20 mol of alkylene oxide condensations 2-C 10Alkyl phenol; The list of ethylene glycol-and two-fatty acid ester; Glycerine monofatty ester; Sorbitol anhydride, list-C 8-C 20Fatty acid and two-C 8-C 20Fatty acid; With polyoxyethylene sorbitol acid anhydride and their combination.APG and glycolipid fat amide (for example methyl glucose amide) also are the non-ionic emulsifiers of being paid close attention to.The anionic emulsifier of being paid close attention to comprises soap, alkyl ether sulphate and sulphonic acid ester, alkyl sodium sulfate ester and alkyl sulfonate esters, benzene sulfonamide acid esters, sulfosuccinic dialkylaminobenzoic acid and dialkyl, hydroxyethylsulfonic acid. C 8-C 20Acyl ester, C 8-C 20Alkyl ether phosphate, alkyl ether carboxylate and combination thereof.
When needed, can comprise antiseptic in the compositions, for example to prevent having harmful microbial growth.Arrcostab, hydantoin derivatives, propionate and the multiple quaternary ammonium compound of the antiseptic of being paid close attention to comprises right-hydroxy benzoic acid.The concrete antiseptic of being paid close attention to includes but not limited to: carbamic acid iodo propinyl butyl ester, phenyl phenol, nipagin, propyl parabene, imidazolidinyl urea, dehydro sodium acetate, benzyl alcohol, benzyl hemiformal, p-hydroxybenzoic acid benzene methyl, 5-bromo-5-nitro-1; 3-diox, 2-bromo-2-nitropropane-1; Between the disodium salt of 3-glycol, ethohexadiol, ethylhexyl glycerol, phenyl phenol sorbic acid, nipagin, propyl parabene, aethyl parabenum, Butyl Chemosept, sodium benzoate, potassium sorbate, ethylenediaminetetraacetic acid, chloroxylenol, DMDM Hydantoin, carbamic acid 3-iodo-2-propyl group butyl ester, chlorhexidine digluconate, phenyl phenol, diazonium ureine, Biguanide derivative, calcium benzoate, calcium propionate, ethohexadiol, Biguanide derivative, Captan (captan), chlorhexidine diacetin, chlorhexidine digluconate, chlorhexidine dihydrochloride, chloroacetamide, methaform, right-chloro--cresol, benzyl chlorophenol (chlorophene), chlorine thyme camphor, chloroxylenol ,-cresol, neighbour-cresol, DEDM hydantoin, DEDM hydantoin two lauric acid salt, dehydroactic acid, diazonium ureine, dibromopamidine diisethionate (dibromopropamidine diisethionate), DMDM Hydantoin etc.When having antiseptic, by the weight of compositions, its amount scope in compositions can be 0.01% to about 10%.
Thickening agent or viscosity modifier can be included in the delivering compositions.The thickening agent of being paid close attention to includes but not limited to: polysaccharide, and like starch, natural/rubber polymer and cellulose.The starch of being paid close attention to includes but not limited to converted starch, like starch ocentyl succinic aluminum.The glue of being paid close attention to includes but not limited to: xanthan gum, sclerotium, pectin, karaya, arabic gum, agar, guar gum, carrageenan, alginate and combination thereof.Suitable cellulose includes but not limited to: hydroxypropyl cellulose, hydroxypropyl emthylcellulose, ethyl cellulose and sodium carboxymethyl cellulose.Synthetic polymer also is the further effectively thickening agent of class.This class comprises Acusol772 Acusol771 (like carbomer (Carbomers)) and polyacrylamide (like Sepigel
Figure BPA00001496795600321
305).When having thickening agent, the scope of its amount can be 0.001 to 5 weight %, like 0.1 to 2 weight %, comprises 0.2 to 0.5 weight %.
In some cases, can have natural or synthetic organic wax, for example one or more are natural or synthetic wax, like animal, plant or mineral wax.In some cases, the melting range of this wax as 30 to 100 ℃, comprises 35 to 75 ℃ at 20 to 150 ℃.The example of this wax comprises the wax such as polyethylene or synthetic wax; Or various vegetable waxs;, Fructus Vitis viniferae wax cured like candleberry, the wax Radix Euphorbiae Pekinensis, ceresine, Robinia pseudoacacia L., Cera Flava, pure white ceresine, cetyl, floral wax, mandarin orange wax, palm wax, Jojoba wax, Japan wax, polyethylene, crystallite, Testa oryzae, lanolin wax, ermine wax, montan wax, candleberry, coronule coconut palm (ouricury), ceresine, palm kernel wax, paraffin, shea wax, Fructus Mali pumilae wax, shellac wax, Salvia japonica Thunb. wax, useless paddy and gather the alkane diol, derivatives is like PEG6-20 Cera Flava or PEG-12 palm wax; Or fatty acid or aliphatic alcohol, comprise its ester, smart like hydroxy stearic acid (for example 12-hydroxy stearic acid), tristearin and three mountain Yu.That is also paid close attention to has; Lattice Shandong Cortex cocois radicis seed fat (Acrocomia Aculeata Seed Butter); Semen Armeniacae Amarum fat; Aloe resin; Semen Armeniacae Amarum (Apricot Kernel) fat; Argan fat; U.S.'s oil palm (Attalea Maripa) seed fat; American Avocado Tree fat; Ba Basu palm fruit fat; But bag fat (Bacuri Butter); The Bagura palmitin; The monkey-bread tree palmitin; Bassia butyracea seed fat; Bassia latifolia seed fat; Seed of black currant fat; Brazil's nut fat; Ka Molina fat; Flos Camelliae Japonicae fat; The wax euphorbium; Palm wax fat; Brazil's Semen Hydnocarpi (Carpotroche Brasiliensis) seed fat; Flos Chrysanthemi fat; Cocoa butter; Cocoa butter; Crema; The Cotton Gossypii palmitin; Cranberry fat; Simple and unsophisticated Ah's Formocarbam fat; Semen Vitis viniferae fat; Hazel nut fat; Fiber crops seed fat; Horse hair fat; Mist ice grass grease; Gabon is according to Ramulus Et Folium Picrasmae core fat (Irvingia Gabonensis Kernel Butter); Jojoba butter; Shea butter; Candle fruit fat; Bu Kui fat (Kukui Butter); Lavender fat; Fructus Citri Limoniae fat; Citrus aurantium Linn. fat; Macadimia nut fat; Mango butter; Ma Lula fat; Mo Nuoyi fat; Mowrah fat; Mu Kaya fat; Astrocarya murumuru fat; The inferior fat of Lay; Fructus Canarii albi fat; Orange fat; Petiolus Trachycarpi oil; Passifolra edulis fat (Passion Butter); Phulwara fat; Fructus Pistaciae Verae fat; Punica granatum L. fat; Fructus Cucurbitae moschatae fat; Fructus Rubi fat; Rice fat; Sa Er fat; Sapucainha fat; Semen Sesami fat; Adeps Bovis seu Bubali resin; Big bean oil fine jade precipice Caulis et folium euphorbiae milii fat; Semen Helianthi fat; Semen pruni armeniacae fat; Fructus Citri tangerinae fat; Tucuma seed fat; Cera Flava resin and Fructus Hordei Germinatus fat.
Coloring agent, spice and abrasive material also can be included in the delivering compositions.The scope that these materials are every kind can be 0.05 to 5% weight, like 0.1 weight % and 3 weight %.The coloring agent of being paid close attention to comprise titanium dioxide (suitably under the situation through surface treatment; With reference to the color index under the CI 77,891 coding), manganese violet (CI 77,742), (CI 77 for ultramarine; 007), (CI 77 for chromium oxide; 288), hydrated chromium oxide (CI 77,289), barba hispanica (CI 77,510), zinc oxide, zirconium dioxide.The concrete coloring agent of being paid close attention to comprises: D & C red No. 19 (CI 45,170), D&C red No. 9 (CI 15,585), red No. 21 (CI 45 for D&C; 380), D&C orange No. 4 (CI 15,510), red No. 27 (CI 45 for D&C orange No. 5 (CI 45,370), D&C; 410), (CI 15,850:1), red No. 6 (CI 15 for D&C for red No. 7 of D&C red No. 13 (CI 15,630), D&C; 850:2), D&C yellow No. 5 (CI 19,140), orange No. 10 (CI 45 for D&C red No. 36 (CI 12,085), D&C; 425), D&C yellow No. 6 (CI 15,985), D&C red No. 30 (CI 73,360), red No. 3 (CI 45 for D&C; 430), white carbon black (CI 77,266), carmine (CI 75,470), natural or synthesis of melanin and aluminum color lake.
The spice of being paid close attention to comprises: the Alba fir needle oil; Acetaldehyde; Acetanil; Acetic acid; Achillea millefolium oil; Fructus actinidiae chinensis (kiwi fruit) fruit water; Adipic acid; Agar; Denatured alcohol; Algin; Folium Aloe; Pentyl acetate; Amyl benzoate; Amyl cinnamic aldehyde; Anethole; Anise alcohol; Anthemidis flos water; Benzaldehyde; Benzyl alcohol; Betula platyphylla Suk. oil; Boswellia serrata tree oil; Butyl acetate; Butyl lactate; The Calendula officinalis caul-fat; Leaf of tea tree water; Camphora; Capsaicin; Cedrol; Cinnamic aldehyde; Citral; Citronellol; LAIMENG (Citrus aurantium Linn.) oil; Fructus Citri sinensis (Citrus) oil; Fructus Citri grandis (grapefruit) oil; Tangerine (Citrus) peel oil; Coumarin; DAA; Ethyl cinnamate; Ether; Eucalyptus Dianthus chinensis (Flos Caryophylli) caul-fat; Farnesol; Fructus Gardeniae oil; Wild Flos Pelargonii oil; Jasminolene; Foral; Anistree (Fructus Foeniculi) oil; Isoamyl acetate; Juniperus mexicana oil; Bay oil; Narrow leaf lavandula angustifolia (Garden lavender) oil; Melaleuca Alternifolia (Camellia sinensis) leaf oil; The lemon-balm leaf oil; Ocean Herba Menthae (Herba Menthae) oil; Menthol; Beta naphthal; Origanum majorana L. (Origanum majorana) leaf oil; The Radix Ginseng extract; N-nonanoic acid; The Flos Pelargonii caul-fat; Lapland pine (Pinus Silvestris Cone) oil; Apricot (Fructus Pruni) core oil; Canis familiaris L. Flos Rosae Multiflorae caul-fat; Herba Rosmarini Officinalis (Herba Rosmarini Officinalis) leaf oil; Lignum Santali Albi (sandalwood) oil; Herba thymi vulgaris (Herba thymi vulgaris) oil; Vanillin; Fructus Vitis viniferae (Fructus Vitis viniferae) leaf oil; Rhizoma Zingiberis Recens (Rhizoma Zingiberis Recens) root oil.
The semi-solid delivery compositions
The semi-solid delivery compositions of being paid close attention in addition is like gel, cream and ointment.This compositions can be the mixture of (except activating agent-calcium phosphate granules complex, also having) water, water-soluble polymer, antiseptic, alcohol, multivalence alcohol, emulsifying agent, wetting agent, wax, solvent, thickening agent, plasticizer, pH value regulator, water-retaining agent etc.In addition, this compositions also can contain other physiologically acceptable excipient or other accessory additive, like spice, dyestuff, emulsifying agent, buffer agent, antibiotic, stabilizing agent etc.The example of these types of compounds provides hereinbefore.
Topical plaster
The solid preparation of being paid close attention in addition is like the topical plaster preparation.The topical plaster preparation can be very different.The topical plaster preparation can comprise active agent layer, supporter and release liner.Active agent layer can comprise a certain amount of activating agent-particle composites in substrate, its mesostroma can comprise following one or more; Binding agent is like pressure sensitive elastomer and acrylic acid; Hydrogel; Physiologically acceptable excipient or other accessory additive are like spice, dyestuff, emulsifying agent, buffer agent, antibiotic, stabilizing agent etc.Supporter can be processed by flexible material, and said flexible material can adapt to the motion of human body, comprises for example plastic foil, various supatex fabric, Woven fabric, spandex etc.Can use various inert blankets, it comprises the various materials that hereinafter described can be applicable to Gypsum Fibrosum.Perhaps, can use non-woven or weave cover layer, particularly allow the elastomer cover layer of heat and vapor transmission.These cover layers can be realized the cooling of painful area, and this provides better comfort, protect gel simultaneously in order to avoid removed by machinery.Release liner can be processed by any material easily, and wherein representational mould release membrance comprises polyester, like PET or PP etc.
Aerosol combination
The aerosol combination preparation of being paid close attention to of using via suction in addition.The propellant accepted that can these aerosol formulations be placed pressurization is like dichlorodifluoromethane, propane, nitrogen etc.Also can they be mixed with and be used for non-pressurised preparation, as be used for aerosol apparatus or nebulizer.In some embodiments, said preparation is the powdery aerosol formulation, and it comprises that the activating agent that suspends or be dispersed in propellant or propellant and the solvent combines granule.Propellant can be the mixture of liquefied chlorine fluorohydrocarbon (CFC), selects the liquefied chlorine fluorohydrocarbon so that required vapour pressure and preparation stability to be provided.Propellant 11, propellant 12 and propellant 114 are to be used for sucking the most widely used propellant of using of aerosol formulation.Other propellant commonly used comprises propellant 113, propellant 142b, propellant 152a, propellant 124 and dimethyl ether.Chemical compound 1,1,1,2-tetrafluoroethane also are the propellants commonly used that is used for the medicinal aerosol formulations preparation.Propellant can be 40% to 90% of total composition for inhalation weight.
The method for preparing of delivering compositions
Aspect of the present invention further comprises the method for preparing of delivering compositions.Though can adopt any suitable fabrication scheme, in some cases, fabrication scheme comprises and at first prepares activating agent-particle composites.After preparation activating agent-particle composites, adopt any suitable scheme that resulting complex is merged in the delivering compositions component then.
Can adopt any suitable scheme to prepare activating agent-particle composites.A kind of scheme of being paid close attention to comprises the fluid composition that at first prepares activating agent; Like the waterborne compositions of activating agent, fluid composition and the spherical nanoporous calcium phosphate granules of a certain amount of even rigidity are merged (stirring as required) being enough to produce under the condition of required activating agent-particle composites then.Thus, in certain embodiments, for example the not combination particle slurry in the proper solvent system (like water or non-aqueous solvent system) and proper amount of activating agent merge will not combine particulate fluid composition.
Pretreatment of particles
As required, before merging, can not carry out pretreatment to combining granule by certain mode with activating agent.Thus, activating agent combines particulate preparation can comprise pre-treatment step, like initial pH value regulating step.In this step, do not combine granule to contact and, be incorporated into particulate required activating agent so that provide with its modification with one or more reagent such as pH value regulator through making.As adopt pH value to regulate, then its specific nature changes according to being incorporated into the type of particulate activating agent.One type of activating agent being paid close attention to is such activating agent, and it comprises acidity and/or alkaline live part, and molecular mass is greater than thousands of Doltons, and for example molecular mass is 3000 Doltons or bigger; Like 5,000 Doltons or bigger, for example 10,000 Doltons or bigger, 25; 000 Dolton or bigger, 50,000 Doltons or bigger, 75,000 Doltons or bigger, 100; 000 Dolton or bigger, 250,000 Doltons or bigger, 500,000 Doltons or bigger, 750; 000 Dolton or bigger, 1,000,000 Dolton or bigger.The example of this activating agent includes but not limited to protein, nucleic acid and polysaccharide.This activating agent can take place to combine by force under the pH value condition of wide model with particulate calcium and/or phosphate radical position.Therefore, for the activating agent of these types, can implement or can not implement pH value as required and regulate.Under the situation that needs pH value to regulate, can for example acid or base reagent be implemented pH value and are regulated through using any suitable pH value regulator.The pH value regulator of being paid close attention to includes but not limited to: lactic acid, glycolic, triethanolamine and sodium hydroxide.In some cases, select not stop the pH value regulator of particulate calcium and/or phosphate radical binding site.
The another kind of activating agent of being paid close attention to is such activating agent, and it comprises acidity and/or alkaline live part, and molecular mass is no more than thousands of Doltons, and for example molecular mass is 2500 Doltons or littler, like 1500 Doltons or littler.The example of this activating agent includes but not limited to organic acid and amines.This activating agent combines with granule under specific pH value.As required, can adopt through optimizing pretreatment of particles that pH value carries out and/or adding specific ionic compound to binding soln (being described in more detail in hereinafter) lining.
The another type activating agent of being paid close attention to is the soluble small molecular with non-charged or weak live part.The example of this chemical compound includes but not limited to: sugar, glucosides and amino acid derivativges.About this type of activating agent, as required, can make use and/or ORGANIC SOLVENT MIXTURES, like ethanol/water or acetonitrile/water, be used for pretreatment and activating agent and combine.
One type of activating agent again of being paid close attention to is the soluble small molecular with hydrophobic part.For this activating agent; Pretreatment can comprise that the reagent that makes granule and surface modifier for example comprise one or more charged groups and one or more hydrophobic tail contacts, and said reagent is such as but not limited to sodium lauryl sulphate, sodium lauryl sulfate and lauryl sodium phosphate etc.
One type of activating agent again of being paid close attention to is the water-insoluble molecule.The example of the water-insoluble molecule of being paid close attention to includes but not limited to: amino acid derivativges, polyphenol and retinoid.For this activating agent, as required, can like use ethanol and dimethyl sulfoxide (DMSO), and/or can use the loading solvent with an organic solvent as pretreating agent.
In some cases, with the ion modification agent granule is carried out pretreatment.The ion modification agent includes but not limited to: the calcium ion modification agent, and like CaCl 2Phosphate anion modifier, like sodium phosphate, or the like.
After any pretreatment of particles step, for example, as stated, in some embodiments, make granule stand washing step.For example, in some cases, desirable is before activating agent combines, to remove unnecessary salt or ion in the degranulation through washing, filtration or decant granule.This step can be adopted any suitable washing scheme and fluid.
Complex forms
After carrying out any pretreatment and/or washing,, make not combine granule and activating agent to merge to combine granule with the generation activating agent such as (if necessary) as stated.As required, the form of activating agent can be powder or solution.Merge activating agent and granule and can adopt any suitable scheme, as in container, carrying out simple static mixing etc.The pH value of compositions is to provide maximum combination, for example through using the pH value regulator, as stated during can selecting to combine.For example, in some cases, alkaline activating agent and granule are merged, acidic active agent and granule are merged.Therefore, complex formation reaction pH value can be in 5 to 14 scope in some cases.In some cases, pH value is 10 or littler, wherein looks complex and forms used duration, can select pH value so that avoid the granule degraded basically, for example can be chosen as 5.2 or bigger.
As implied above, can use any The suitable solvent system for preparation activating agent-particle composites.As implied above, activating agent is combined with granule can be different to produce the used dicyandiamide solution of activating agent-particle composites.The dicyandiamide solution that can be applicable to prepare activating agent-particle composites can be by single solvent or two kinds or more kinds of different solvent composition.Be present in solvent in the dicyandiamide solution of being paid close attention to and can be polar (promptly; They have 15 or bigger dielectric constant) or nonpolar (promptly; They have the dielectric constant less than 15), (they make anion (electronegative solute) solvation consumingly via hydrogen bond like this) of protic or aprotic (that is, they have enough big dipole moment with via their dipole with the material solvation of positively charged).
The proton solvent of being paid close attention to includes but not limited to: alcohol, like methanol, ethanol, propanol, isopropyl alcohol, butanols, amylalcohol, hexanol, enanthol, capryl alcohol, trifluoroethanol, phenol, benzyl alcohol, glycerol, ethylene glycol, diethylene glycol; Carboxylic acid/amide is like formic acid, acetic acid, lactic acid, propanoic acid, trifluoroacetic acid, Methanamide; Amine is like ammonia, diethylamine, butylamine, propylamine; And water.The aprotic solvent of being paid close attention to includes but not limited to: hydrocarbon, like pentane, hexane, heptane, cyclohexane extraction, hexahydrotoluene, decahydronaphthalene; Ketone/aldehyde is like acetone, methyl ethyl ketone (MEK), methyl iso-butyl ketone (MIBK), butanone, pentanone, Ketohexamethylene, benzaldehyde; Aromatic compound, like benzene, toluene, benzotrifluoride, xylene, methyl phenyl ethers anisole, chlorobenzene, aniline, N, accelerine, benzonitrile; Ether is like dimethoxy-ethane, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether(MTBE) (MTBE), oxolane 、 diox, glyme, diethylene glycol dimethyl ether, Polyethylene Glycol (PEG), PEG ester, PEG anhydro sorbitol, PEG ether, PEG ester, polypropylene glycol (PPG), PPG ester, alkoxylate straight chain alkane glycol, alkoxylated alkyl glucose ether, PPG alkyl ether; Ester/amide is like methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, ethyl benzoate, phenylamino benzoic acid methyl ester, dimethyl phthalate, dibutyl phthalate, dimethyl acetylamide, dimethyl formamide (DMF); Nitrile is like acetonitrile; Carbonic ester is like DMC dimethyl carbonate, diethyl carbonate, Allyl carbonate, ethylene carbonate; Halogenated compound is like carbon tetrachloride, chloroform, dichloromethane, dichloroethanes, trichloroethane, freon-11, BMIM-PF 6Ionic liquid; Sulfur-bearing/phosphorus compound is like dimethyl sulfoxide (DMSO), Carbon bisulfide, sulfolane, hexamethyl phosphoramide (examethylphosphramide); And amine, like pyridine, triethylamine, N-Methyl pyrrolidone (NMP).
As required, can carry out modification to dicyandiamide solution, as with buffer agent, pH value regulator (acid or alkali), hydrophilic molecules, hydrophobic molecule or have hydrophobic group concurrently and the molecule of hydrophilic group (for example, surfactant) carries out modification with one or more modifier.The buffer agent of being paid close attention to includes but not limited to: HCl/ sodium citrate, citric acid/sodium citrate, acetic acid/sodium acetate, K 2HPO 4/ KH 2PO 4, Na 2HPO 4/ NaH 2PO 4, Borax/sodium hydroxide; And biological buffer; For example; TAPS (3{ [three (methylol) methyl] amino } propane sulfonic acid), N-two (ethoxy) glycine (N; Two (2-ethoxy) glycines of N-), Tris (trihydroxymethylaminomethane), Tricine (N-three (methylol) methyl glycine), HEPES (4-2-ethoxy-1-piperazine ethyl sulfonic acid), TES (2-[three (methylol) methyl] amino) ethyl sulfonic acid), MOPS (3-(N-morpholino) propane sulfonic acid), PIPES (piperazine-N, N-two (2-ethanesulfonic acid), dimethyl arsenate salt (cacodylic acid), SSC (saline sodium citrate) and MES (2-(N-morpholino) ethyl sulfonic acid); Or the like.
Can be according to component and the character that will select concrete dicyandiamide solution with one or more character of the compound activating agent of granule, like pH value, composition, temperature etc., wherein this character can comprise activating agent dissolubility, structure, pKa, logP etc.
After preparation activating agent-particle composites, adopt any suitable scheme that resulting complex and delivering compositions component are merged then.The concrete scheme that is adopted can be different, and this depends on the character of delivering compositions component, wherein can merge to produce required delivering compositions through the granule that mixes delivering compositions component and supported active agent in some cases.Though the temperature during merging can change to some extent, temperature is 80 ℃ in some cases, as 40 ℃ or lower, as 30 ℃ or lower, room temperature or colder for example.The amount of the activating agent-particle composites that merges with delivery vector can be different.In some embodiments; The amount of the activating agent-particle composites that merges with delivery vector is enough to produce so final delivering compositions; In said delivering compositions, concerning every gram delivering compositions component, the scope of the amount of activating agent-particle composites is 0.001mg/g to 1000mg/g; For example 0.1mg/g to 200mg/g comprises 1mg/g to 50mg/g activating agent-particle composites.In certain embodiments, avoid the existence of chelating agen.The pH value of preparation is 5.0 or bigger, as 5.5 or bigger.
Practicality
Delivering compositions of the present invention can be applicable to the method to experimenter's local location active agent delivery, and local location wherein can be skin surface position or mucosa position.To experimenter's local location active agent delivery the time, delivering compositions of the present invention can be delivered to activating agent-particle composites in the epidermis position of experimenter's skin surface below at least.Thus, embodiment of the present invention comprise that wherein this method can cause complex is delivered in experimenter's the deep horny layer and/or corium with the particle delivery of the supported active agent method in experimenter's horny layer." in horny layer " expression complex is delivered to the zone of at least 1 cellular layer below the skin surface." deep horny layer " is meant 2 or the zone of more a plurality of cellular layers below the skin surface, like 5 below the skin surface or more a plurality of cellular layer, comprises 10 or more a plurality of cellular layer below the skin surface.In some cases, complex is delivered to 2 μ m below the skin surface or darker horny layer zone, like 5 μ m or darker, comprises 15 μ m or darker horny layer zone.
Embodiment of the present invention comprise that wherein said method can cause complex is delivered in experimenter's the corium with the particle delivery of the supported active agent method in experimenter's horny layer." in corium " is meant that complex is delivered to the zone of at least 20 cellular layers below the skin surface.
When arriving their target skin site, in some cases, activating agent combines granule just to begin to discharge its activating agent " payload ".The release of activating agent from granule can take place according to many different mechanism.For example, the environment of skin can reverse reagent to particulate any binding interactions.Scheme except this mechanism or instead; The environment of skin can destroy calcium phosphate granules (for example, the dissolving that causes through the pH value gradient by skin), makes the spherical nanoporous granule of even rigidity under acid condition; Be 5 or lower for example at pH value; As 4.5 or lower, comprise 4.3 or lower condition under, as under cuticular physiological phenomenon condition, dissolving.Granule dissolves the required time in horny layer can be different; 1 minute to 72 hours scope,, comprise 30 minutes to 12 hours in certain embodiments as 10 minutes to 24 hours; Through this period, activating agent is combined to discharge the granule from activating agent.Aspect of the present invention comprises the release of all activating agents.
Therefore method of the present invention causes bioactive agent delivery is delivered in experimenter's at least the horny layer.In some embodiments, activating agent is retained in the horny layer to bring into play its required activity.Also in other embodiments, activating agent can be in one or more other its required activity of target location performance of health.The other target location of being paid close attention to comprises other cuticle region, such as but not limited to clear layer, granulosa, spinous layer (stratum spinusom), basal layer and corium.In certain embodiments, activating agent is delivered to dermal zone.In certain embodiments, activating agent is delivered to the zone below the corium, for example in the subcutaneous tissue.
In some cases, can with the activating agent general send to the experimenter.When activating agent by general when sending to the experimenter, reached the treatment blood plasma level of activating agent.The treatment blood plasma level of activating agent can be different, and this depends on concrete activating agent and the disease that will treat.In certain embodiments, the therapeutic activity level that is reached like 1pg to 20 μ g, like 1ng to 1 μ g, comprises 10ng to 100ng in the scope of 0.1pg to 100 μ g.
When the method for embodiment of the present invention, delivering compositions is applied to experimenter's regional area, and by being enough to cause required mode to experimenter's active agent delivery to remain on this regional area as stated.In certain embodiments, said regional area is the keratinized skin zone.The keratinized skin zone comprises hair follicle, sweat gland and sebaceous gland, can be present in various intact or impaired skin site places, and the position of wherein being paid close attention to includes but not limited to: extremity, arm, hands, lower limb, foot; Trunk, for example breast, the back of the body, abdominal part; Head, for example cervical region, face; Or the like.In certain embodiments, said zone is a head zone, like facial zone, for example around forehead, occipital bone zone, the oral area etc.Area about the regional area of using compositions can be different, is 1mm in certain embodiments 2To 300cm 2Or bigger, like 1cm 2To 50cm 2, comprise 3cm 2To 10cm 2
When implementing described method, can in the given time period, use single dose or two or more dosage to the experimenter.For example, given one month treatment phase, can use one or more dosage to experimenter's local location; Like 2 or more dosage; 3 or more dosage, 4 or more dosage, 5 or more dosage etc.; Dosage wherein can weekly or be used every day, perhaps even can use repeatedly every day.
With activating agent is not to compare with the matched group that the composite form of calcium phosphate granules is sent, can give one or more advantages according to sending of activating agent complex of the present invention.For example, in some cases, activating agent is stabilized in calcium phosphate complex, thereby its activity is held.In some cases; With according to the form of the complex of embodiment of the present invention with activating agent and calcium phosphate granules compound can with bioactive agent delivery deliver to send under the normal condition less than the position; For example be delivered in the horny layer; And if said activating agent is not to be present in the calcium phosphate granules complex, then send being limited to skin surface.In some cases, compare with suitable matched group, method of the present invention causes the infiltration of activating agent to strengthen.Suitable matched group can be for comprising the delivering compositions of identical activating agent and delivery vector component, but do not have the spherical nanoporous calcium phosphate granules of even rigidity.In some cases, compare with this matched group, the enhancing of infiltration reaches 2 times or more, as 5 times or more, comprises 10 times or more.Also in other embodiments, complex serves as the controlled release storehouse of activating agent from horny layer, thereby the required slow release and the delivery curves of activating agent are provided.
Though the purposes of mainly using with regard to dermal delivery has in this article been described activating agent-calcium phosphate complex, they are used to other application in some cases.For example, activating agent-calcium phosphate complex of the present invention can be applicable to the non-dermal delivery activating agent to the experimenter in some cases.The example of non-dermal delivery preparation includes but not limited to: capsule, tablet, pill, group's agent, lozenge, powder, granule, syrup, elixir, solution, suspension, emulsion, suppository or its slow releasing preparation, or any other form that is suitable for administration.In some cases, the pharmaceutical composition of using by conventional program is configured to the form that is fit to the people is carried out oral or intravenous administration.The suitable pharmaceutical carrier and the example of compound method thereof are described in Remington's the 86th, 87,88,91 and 92 chapters of " The Science and Practice of Pharmacy; Alfonso R.Gennaro compiles; Mack Publishing Co.Easton, Pa., the 19th edition; 1995 ", and foregoing is incorporated this paper by reference into.
In certain embodiments, provide calcium is delivered to the method in the horny layer at least.In these methods, the calcium phosphate granules that the present invention is complete be delivered to cuticular at least in, for example, as stated." complete " is meant that granule is abundant complete int granule.Thus, they will be different from the granule that has contacted with chelating agen such as EDTA, and in the latter case, chelating agen is for example through destroying particulate structure with the chelation of calcium ion.In these embodiments, calcium phosphate granules can not contain any bonded activating agent, for example they be not with the bonded calcium phosphate granules of activating agent.In these embodiments, the delivery vector component can not contain for example EDTA of any chelating agen.These methods can be applicable to any suitable purpose is delivered to calcium in the said at least layer, and can the experimenter that calcium is delivered in the horny layer at least be implemented expectation.Can use any above-mentioned delivery vector, what wherein paid close attention to is the carrier that does not contain chelating agen.
Said method and composition can be used for various different types of animals; Wherein said animal is " mammal " or " mammal " normally, and wherein these terms are widely used in and describe Mammalia with interior organism, (for example comprise the carnivore order; Canis familiaris L. and cat), Rodentia (for example; Mice, Cavia porcellus and rat), Lagomorpha (for example, rabbit) and Primates (for example, people, chimpanzee and monkey).In certain embodiments, experimenter or patient are the people.
Following examples are that the mode unrestricted with explanation provides.
Experiment
The preparation and the sign of the spherical nanoporous calcium phosphate granules of I. even rigidity
A. preparation
Prepare calcium phosphate nano-crystal slurry through under the controlled condition of temperature, pH value, pressure, gas, mixing speed, reagent concentration, interpolation speed and ageing time, the phosphate compound water solution being added drop-wise in calcium complexes aqueous solution or the suspension.The drive nozzle type spray dryer that has a solution-air fluid tip through use with the slurry spray drying to form spherical porous powder.300 ℃ to the temperature of 900 ℃ of scopes with gas or electric furnace or kiln with a period of time of 1 to 24 hour of dried powder sintering.
B. characterize
Figure 1A and 1B show the loose structure of the spherical nanoporous calcium phosphate granules of resulting 2 microns even rigidity (preparation as stated), use SEM (A) 10,000X, (B) 50,000X.Fig. 2 A and 2B show the outside and the internal structure of 2 microns spherical nanoporous calcium phosphate granules of even rigidity (preparation as stated), use SEM (A) and TEM (B) (15000X).Big (25-50m 2/ g) internal surface area and external surface area are sizable, this provides and the bonded high power capacity of activating agent.Fig. 3 shows particle grain size distribution, and it is measured through Coulter Multi-sizer 3 particle collectors, and confirms through scanning electron microscope.Particle mean size is 2 μ m.
C. the safety of calcium phosphate granules
Figure BPA00001496795600431
II. the preparation of activating agent-calcium phosphate granules complex
A. the general combination criterion that comprises some activating agent pretreatment
Calcium phosphate granules combines biomolecule widely, and in some cases with they stabilisations.With calcium phosphate granules combine to be based on ionic interaction.The functional group of calcium phosphate granules is by the calcium ion (Ca of positively charged ++) and electronegative phosphate anion (PO4 -3) form.The amount that this means the anionization carboxyl of biomaterial will reduce under acid condition.Therefore combining and to weaken between the calcium ion of the anionization carboxyl of biomolecule and calcium phosphate granules.Interaction under alkali condition between the phosphate radical functional group of and calcium phosphate granules amino for the cationization of biomolecule, situation is opposite.
PH value and ionic strength directly influence combining between calcium phosphate granules and the biomaterial.Calcium phosphate granules can combine the biomaterial of extensive molecular weight (for example, 200 to 10,000,000) and isoelectric point, IP (for example, 2.0 to 12).
Except pH value and ionic strength, the molecular weight of biomaterial, shape and orientation also influence the combination to calcium phosphate granules.For example, the BSA with relatively low molecular weight combines with 90mg/g, and the DNA with relatively large molecular weight combines with calcium phosphate granules with the ratio of 1mg/g.The binding ability of mcroorganism molecule such as DNA is by the external surface area decision of calcium phosphate granules.Generally speaking, the bonded major parameter that influences between calcium phosphate granules and the biomolecule has pH value, ionic strength, stereochemical effect and molecular weight.
B. concrete activating agent-calcium phosphate granules complex
1.pH value is to bonded influence
A. salicylic acid
Material:
Calcium phosphate granules
Salicylic acid, Fisher Scientific company, model A277-500
Method:
I. the 23.2mg salicylic acid is dissolved in the 1ml ethanol.
Ii. the 4g calcium phosphate granules is suspended in the 39.8ml water, pH value is adjusted near the target pH value with HCl.
Iii. in the suspension of calcium phosphate granules, mix 0.2ml salicylic acid solution (23.2mg/ml).
Iv. with HCl pH value is adjusted to each target pH value (11.36,8.34,7.47,7.07,5.99).
V. under each pH value, from suspension, get the 4.8ml sample.All samples centrifugal 10 minutes separately with 2000 * g.
Vi. measure the absorbance of supernatant down at 297nm (salicylic detection wavelength) through the UV spectrophotometer.
Vii. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
The result is shown in the following table, shows that salicylic acid combines with calcium phosphate granules with the pH value dependency mode that is driven by salicylic pKa.
Figure BPA00001496795600441
B. polyphenol complex (PPC) is to calcium phosphate granules
Material:
Calcium phosphate granules
Polyphenol complex (PPC)
Method:
I. the PPC with 33.98mg is dissolved in the 6.8ml water.
Ii. the 2g calcium phosphate granules is suspended in the 19.9ml water, pH value is adjusted to 9.62 with HCl.
Iii. the PPC solution (5mg/ml) that in the suspension of calcium phosphate granules, mixes 0.1ml; Get the 2ml sample.
Iv. with HCl pH value is adjusted to each target pH value (8.58,8.07,7.49,7.21,6.75,6.08).
V. under each pH value, from suspension, get the 2ml sample.All samples centrifugal 10 minutes separately with 2000 * g.
Vi. measure the absorbance of each supernatant down at 280nm (the detection wavelength of PPC) through the UV spectrophotometer.
Vii. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
The binding ability of calcium phosphate granules is summarized in following table.The result shows that PPC combines under any pH value, to carry out, and is therefore irrelevant with pH value.
pH Bonded PPC (μ g/g)
9.62 242.5
8.58 242.5
8.07 235.0
7.49 215.0
7.21 220.0
6.75 212.5
6.08 197.5
2. the combination embodiment that has the protein active substances of different molecular weight (MW) and isoelectric point, IP (pI)
A. bovine serum albumin (BSA) (MW:66KD, pI:4.7)
Material:
Calcium phosphate granules
BSA, freeze-dried powder, Fisher Scientific company, production code member BP-671-10
Method:
I. the 0.5g calcium phosphate granules is suspended in the 1ml water, with HCl pH value is adjusted to and is roughly 7.Suspension was mixed 10 minutes.
Ii. be dissolved in BSA in the water and mixing lightly, with preparation 20mg/ml solution.In each calcium phosphate granules suspension, add the BSA solution of 4ml and mixed 30 minutes.Measure the final pH value of suspension.
Iii. with suspension centrifugal 5 minutes with 2000 * g.Supernatant is transferred in the new test tube, and with 2000 * g centrifugal 5 minutes.
Iv. it is quantitative to the BSA in the supernatant that combines suspension to develop size exclusion HPLC method.Use the Phenomenex BioSep in the Shimadzu 10AS system TM-SEC-S3000 post (7.8 * 300mm, 5 μ m) separates.Mobile phase is 100% 50mM phosphate buffer (Na +, pH value 6.8), and with the speed eluting of 1.4 ml/min.At 280nm monitoring eluent.Observe the BSA main peak, about 6.8 minutes of retention time.Proofread and correct the quantitative of realization BSA through external perimysium reference.
V. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
BSA combines with calcium phosphate granules with 95.1mg/g.
B. lactoferrin (MW:90KD, pI:8.5)
Material:
Calcium phosphate granules
The lactoferrin that comes from human milk, Sigma Aldrich company, production code member 0520-100MG
Method:
I. in water, prepare lactoferrin solution with 4.98mg/ml.
Ii. be suspended in the 0.3g calcium phosphate granules in the 1.2ml water and mixed 5 minutes.
Iii. the lactoferrin solution that adds 1.8ml 4.98mg/ml is reaching the ultimate density of 3.0mg/ml, and final volume is 3ml.
Iv. suspension was mixed 30 minutes, and in desk centrifuge with 5000 * g centrifugal 10 minutes.
V. measure the absorbance of supernatant down at 280nm (the detection wavelength of lactoferrin) through the UV spectrophotometer.
Vi. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
Vii. deduct in the supernatant detected lactoferrin amount through the total primary quantity from combine suspension and come the lactoferrin of calculations incorporated.
The result:
Combining with calcium phosphate granules through measuring the 29.63mg/g lactoferrin, is 2.99mg/ml in conjunction with concentration.
C. lysozyme (MW:14KD, pI:10.7)
Material:
Calcium phosphate granules
Lysozyme, MP biomedicals LLC. company, production code member ICN10083405
Phosphoric acid, Fisher Scientific company, production code member A260500
Method:
I. the 364.7mg lysozyme is dissolved in (20.25mg/ml) in 18.01 water.
Ii. the 0.8g calcium phosphate granules is mixed with 4ml water, the pH value of suspension is adjusted to neutrality with phosphoric acid,diluted.
Iii. 4ml lysozyme soln (20.25mg/ml) is added in the suspension of calcium phosphate granules reaching the ultimate density of 10.124mg/ml, and final volume is 8ml.Measure final pH value.
Iv. suspension was mixed 30 minutes, and in desk centrifuge with 2000 * g centrifugal 10 minutes.
V. measure the absorbance of supernatant down at 280nm (the detection wavelength of lysozyme) through the UV spectrophotometer.
Vi. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
Combine with calcium phosphate granules with 6.8mg/g pH value 6.83 times through measuring lysozyme.
3. solvent is to bonded influence
Adapalene
Material:
Calcium phosphate granules
Adapalene, Sekhsaria Chemicals Limited, India
DMSO, Fisher Scientific company, production code member D159-4
Ethanol, Fisher Scientific company, production code member AC61511-0010
Method:
I. adapalene is formed in the saturated solution (0.087mg/ml in ethanol, 20.65mg/ml in DMSO) among ethanol and the DMSO
Ii. the 0.5g calcium phosphate granules is mixed with the ethanol or the DMSO saturated solution of 5ml adapalene.
Iii. suspension was mixed 30 minutes, and in desk centrifuge with 2000 * g centrifugal 10 minutes.
Iv. measure the absorbance of supernatant down at 319nm (the detection wavelength of adapalene) through the UV spectrophotometer.
V. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
Adapalene is 0.78mg/g with the binding ability of calcium phosphate granules in ethanol.Adapalene is 12.55mg/g with the binding ability of calcium phosphate granules in DMSO.
C. the pretreatment embodiment of bioactive substance
With sodium lauryl sulfate pretreatment and the bonded six victory peptides (Argireline) of calcium phosphate granules
Material:
Calcium phosphate granules
Six victory peptides, (acetyl group six peptides-8), Lipotec S.A company
Sodium lauryl sulfate (SLS), Colonial Chemical, Inc. company
Method:
I. six victory peptides are dissolved in and become 10mg/ml solution in the water.
Ii. calcium phosphate granules was mixed 5 minutes with the 0.1%SLS of 10ml.In desk centrifuge with 2000 * g with centrifugal 10 minutes of suspension, remove supernatant.Agglomerate is suspended in the 20ml water again, with centrifugal 10 minutes of 2000 * g and discard the supernatant of washing.Repeat twice of this washing step.Measure the water that contains in the agglomerate.Final agglomerate is used for combining research.
Iii. calcium phosphate granules (handle or handle without SLS through SLS) is mixed with water.Add HCl (or NaOH) and be adjusted to the target pH value, comprise neutral and pH value～10 with pH value with the calcium phosphate granules suspension.
Iv. the six victory peptide storing solutions that in each combination suspension, add 10mg/ml are with the ultimate density to 0.5mg/ml.Final pH value is measured in the suspension mixing after 30 minutes.
V. will combine suspension in desk centrifuge centrifugal 10 minutes with 2000 * g.With the RI-detector that is connected to Shimadzu HPLC 20A system analytically clear liquid with quantitative to the free six victory peptides in the solution.Exploitation size exclusion HPLC method is with quantitative to six victory peptides in the supernatant of binding mixture.Use the Phenomenex BioSep in the Shimadzu 20A system TM-SEC-S3000 post (7.8 * 300mm, 5 μ m) is realized separating.Mobile phase is 100% water, and with the speed eluting of 1 ml/min.Under 205nm or through RI-detector (Shimadzu company, model RID-10A) monitoring eluent.Observe six victory peptide main peaks in the chromatogram, about 14 minutes of retention time.Proofread and correct the quantitative of realization six victory peptides through external perimysium reference.
Vi. deduct in the supernatant detected six victory peptide amounts through the total primary quantity from combine suspension then and come six victory peptides of calculations incorporated.
The result:
Figure BPA00001496795600491
D. visual with the bonded activating agent of calcium phosphate granules
The 0.1g calcium phosphate granules is added in the 0.9% rhodamine B aqueous solution of 1ml, rotates resulting suspension and remove supernatant.Resulting rhodamine B-calcium phosphate granules is following dry 24 hours at 58 ℃.Resulting powder is suspended in sad triglyceride/capric acid triglyceride again, and passes through microscope imaging.Resulting image is shown in Fig. 4 A.Fig. 4 B shows the calcium phosphate granules that has no rhodamine B.
E. other activating agent-calcium phosphate complex
Adopt scheme as implied above, the general introduction in the according to the form below prepares activating agent-calcium phosphate complex.In following table, concrete dicyandiamide solution is the example of operable dicyandiamide solution.
Figure BPA00001496795600492
Figure BPA00001496795600511
Figure BPA00001496795600521
Figure BPA00001496795600531
Figure BPA00001496795600542
Figure BPA00001496795600551
III. the release of activating agent
A.pH value dependent release
1. lysozyme
In horny layer, the pH value scope is 4.3 to 5.0, and pH value reduces along with the cuticular degree of depth.Be similar to release bioactive agent under the condition of skin in order to study calcium phosphate granules, making the buffer 8 hours of two kinds of lysozyme calcium phosphate complexes contact pH value 4.8 (0.5M sodium acetate) and pH value 7.0 (10mM Bis Tris).Make buffer cross sample, and per hour collect, discharge through analyzing lysozyme by UV spectrogrph monitoring 280nm peak with 1 milliliter/hour data rate stream.With etc. the lysozyme calcium phosphate granules complex of quality at the buffer mesoscale eddies of pH value 4.8 always can get lysozyme in the sample estimates.Observe lysozyme 4.8 times at pH value and from calcium phosphate granules, disengage fast, wherein most of lysozyme disengaged in first hour.That compares is following, under the situation of pH value 7, does not observe lysozyme through 8 hours and from calcium phosphate granules, disengages.
B. discharge via the Hydroxysome degraded
1. calcium phosphate granules is in 4.8 times degradeds of pH value
Under two kinds of pH value of 4.8 (0.5mM sodium acetates) and 7.1 (0.1mM Bis Tris), cultivate the 50mg calcium phosphate granules, at room temperature solution was placed on rotary apparatus 96 hours with 2mL.Centrifugal sample, dried particles is also weighed.The percent weight loss of calcium phosphate granules under pH value 4.8 and 7.1 is respectively 12% and 3%.The buffer capacity of this closed system has limited the dissolving fully of calcium phosphate granules.Then in the circulation system with identical buffer research dissolving, wherein make solution lentamente (5 milliliters/hour) flow through sample (50mg) and stir sample lightly, then carry out particulate collection of calcium phosphate granules and drying.After 72 hours, the percent weight loss of calcium phosphate granules granule under pH value 4.8 and 7.1 is respectively 31% and 3%.These results show calcium phosphate granules dissolving under low pH value, and this dissolving is the gentle function towards capacity of solution pH value.
C. activating agent combines with calcium phosphate granules reversiblely, and discharges the activity that does not change activating agent
1.BSA calcium phosphate complex
Prepare the BSA-calcium phosphate complex as stated.With the resulting complex of water washing, handle to discharge any bonded BSA with the 0.2M sodium phosphate then.
Material:
Calcium phosphate granules
BSA, freeze-dried powder, Fisher Scientific company, production code member BP-671-10
Method:
I. the BSA with 0.1170g is dissolved in the 11.7ml water, becomes the solution of 10mg/ml.
Ii. the 0.5g calcium phosphate granules is mixed with the 10mg/mlBSA solution of 5ml.Suspension was mixed 30 minutes, and the final pH pH-value determination pH is neutral.
Iii. with suspension centrifugal 10 minutes with 2000 * g.Supernatant is transferred in the new test tube, and with 2000g centrifugal 10 minutes once more.
Iv. use the final supernatant of Shimadzu 10A HPLC systematic analysis with quantitative BSA and calculations incorporated.
V. will combine the granule of suspension to mix from 5ml with 0.8ml water, and with 2000 * g centrifugal 10 minutes.The granule of rinsing is mixed with 0.8ml water once more, and with 2000 * g centrifugal 10 minutes.
Vi. the granule of final rinsing is mixed with the 500mM sodium phosphate buffer of 2ml (pH value 6.8) and 2.235ml water, in suspension, to discharge BSA with 200mM sodium phosphate.With the centrifugal release suspension of 2000 * g 10 minutes.With Shimadzu 10A HPLC systematic analysis supernatant with quantitative BSA.
V. use the Phenomenex BioSep in the Shimadzu 10AS system TM-SEC-S3000 post (7.8 * 300mm, 5 μ m) realizes that BSA is quantitative.Mobile phase is 100% 50mM phosphate buffer (Na +, pH value 6.8), and with the speed eluting of 1.4 ml/min.The monitoring eluent at the 280nm place.Observe the BSA main peak, about 6.8 minutes of retention time.Proofread and correct the quantitative of realization BSA through external perimysium reference.
Vi. do not having to carry out the matched group experiment by identical program under the situation of calcium phosphate granules.
The result:
Adopt HPLC to analyze the BSA that discharges, and confirm and unconjugated matched group identical (retention time 6.85 minutes), show that combination and the release with calcium phosphate granules does not influence the BSA integrity.
2. tocopherol phosphate ester sodium calcium phosphate complex
Material:
Calcium phosphate granules
Tocopherol phosphate ester sodium (TPNa), Showa Denko KK company
Ethanol, Fisher Scientific company, production code member AC615090020
Method:
I. be dissolved in (0.5mg/ml) in the 40ml water through the TPNa that mixes gently 20mg.
Ii. the 3g calcium phosphate granules is mixed with the 0.5mg/ml TPNa solution of 30ml, mixed 30 minutes.
Iii. will combine suspension centrifugal 10 minutes with 2000 * g.Supernatant is transferred in the new test tube, and once more with centrifugal 10 minutes of 2000 * g with clarification.Under 286nm, analyze final supernatant with quantitative free TPNa and calculations incorporated with the UV spectrophotometer.Be attached to calcium phosphate granules in conjunction with about 100% TPNa in the suspension.
Iv. TPNa calcium phosphate complex agglomerate is suspended in 60% ethanol to discharge bonded TPNa again.
V. with the release suspension in 60% ethanol centrifugal 10 minutes with 2000 * g.With the UV spectrophotometer under 286nm analytically clear liquid with the free TPNa of quantitative release.
The result:
With the TPNa that the UV analysis of spectral method discharges, identical with unconjugated matched group through measuring, this shows with the combination of calcium phosphate granules and discharges does not influence the TPNa integrity.
IV. FORMULATION EXAMPLE
1. calcium phosphate granules-single lactofiavine phosphate ointment formulation
Figure BPA00001496795600571
Figure BPA00001496795600581
Step:
Step 1. is added Cera Flava and Protachem IPP in beaker.Begin to be heated to 70 ℃-75 ℃ up to evenly.Be cooled to 50 ℃.Add SonneNatural TMWith Capmul MCM.Mixing is up to evenly.
Step 2. adds 1% water and single lactofiavine phosphate in independent beaker.Under R.T, mix up to dissolving.Add calcium phosphate granules (pH value being adjusted to 7) with lactic acid.With 500RPM rotation 10 minutes.
Step 3. at room temperature is transferred to step 2 with step 1.Mixing is up to evenly.
B. the stability of activating agent in preparation
1. vitamin C
A. method:
With the 11.9mg dissolution of ascorbic acid in 30ml water.2 grams, 2 μ m calcium phosphate granules are suspended in the 19.5ml water, and pH value are adjusted to 7.14 with HCl.(0.40mg/ml) is blended in the suspension of calcium phosphate granules with the 0.5ml ascorbic acid solution, and this drops to 7.05 with pH value.The calcium phosphate granules suspension (pH value 7.05) that will comprise 10 μ g/ml ascorbic acid was cultivated 0.5 to 5 hour down at 50 ℃.Through suspension is cooled off the thermal denaturation that stopped ascorbic acid in 15 minutes in ice bath.In order to discharge in the calcium phosphate granules bonded ascorbic acid measuring stabilization effect, with HCl the pH value of each suspension is adjusted to 5, and with 3, centrifugal 10 minutes of 000rpm.The supernatant that under 265nm, measures.As contrast, also do not cultivate the ascorbic acid solution of 10 μ g/ml under the situation of calcium phosphate granules and measure having by identical program.Be calculated as follows the activity of ascorbic acid:
The activity of ascorbic acid (%)=(cultivate the A of back supernatant 265nm/ the A of ascorbic acid before cultivating 265nm) * 100
Repeat identical program with 10 μ m calcium phosphate granules.
B. result
The result is summarized in the following table.Be reduced to 36% through cultivating 0.5 hour activity down with ascorbic acid at 50 ℃; When during identical, making ascorbic acid be attached to 2 μ m calcium phosphate granules, this activity is increased to 85%.After 50 ℃ are down cultivated 3 hours, do not have the complete degeneration of ascorbic acid of calcium phosphate granules and do not have activity.Yet, under 50 ℃ during identical 3 hours, the ascorbic acid that is incorporated into 2 μ m calcium phosphate granules has 48% activity.
Time (hour) Contrast (%) 2μm(％)
0 100 100
0.5 36 85
2 18 59
3 0 48
5 0 35
C. in order to obtain the stability in the calcium phosphate complex of active substance in final preparation, have necessity dicyandiamide solution is added other free active substance, this depends on the dissolubility of employed dicyandiamide solution.
V. send research
1. be delivered in the horny layer of human body skin
Certain density calcium phosphate granules water slurry was applied in 10 seconds living person's forearm (Fig. 5) through wiping.Implement cuticular first, second and third layer tape stripping then.Calcium phosphate granules penetrates into cuticular the 3rd layer.
2. be delivered in the cuticular bottom of mouse skin
Calcium phosphate granules infiltration horny layer, and along with granule is cleaved into less replacement part and further is penetrated in the lower layer.Calcium phosphate granules is no longer intact after 7 hours, and no longer is spherical, and this shows the forfeiture of particle integrity property.
A. material:
Use 2 μ m calcium phosphate granules.
B. preparation:
Calcium phosphate granules is suspended in 70% ethylene glycol and 30% ethanol processes 10% suspension.With resulting suspension local application (1 * 1cm area) on the skin surface of hairless mouse.Anesthetized mice between administration time period.Carry out using the first time (0.2ml) and it is kept, carry out using the second time with identical amount in same area after 4 hours.Use after seven hours for the first time and remove skin and use Ca ++Handle.Localization method is according to the EM technology.
C. result:
Before handling with calcium phosphate granules, the inspection epidermis shows, has only in horny layer that do not have in the granulosa zone can detected Ca ++(Fig. 6).After the local application calcium phosphate granules, in horny layer, can see calcium phosphate granules (Fig. 7 A) as stated, minimum granule moves to than (Fig. 7 B) in the deep layer.
3. the detection of activating agent in the horny layer
A. study purpose
The purpose of this research is to be attached to the activating agent of the spherical nanoporous calcium phosphate granules of the even rigidity of 2 μ m described in above embodiment 1 in local application (duomycin CTC) afterwards, detects the activating agent (CTC) in the horny layer.Select duomycin (available from the CTC of Sigma, production number C-4881) to be because it allows to realize the visual of CTC through fluorescence, and therefore can in horny layer, detect through Laser Scanning Confocal Microscope.
B. preparation
CTC through dissolving 80mg in 10ml water processes CTC solution.Through with 3,000rpm removed undissolved CTC in centrifugal 10 minutes.The 200mg granule is mixed with the CTC solution of 2ml and vortex 1 minute.Through the three-wheel washing and then with 3,000rpm removed free CTC in centrifugal 10 minutes.Combine particle suspending in water resulting CTC with 1: 10 dilution ratio.
C. local application
The suspension that will in above-mentioned 3.b, prepare (approximately 0.2ml) local application (11cm area) on the skin of hairless mouse.Anesthetized mice between administration time period.Use Laser Scanning Confocal Microscope (under the 510nm wavelength emission that the 380nm wavelength excites) to check their skin after 7 hours.
D. result
Resulting Laser Scanning Confocal Microscope image is shown in Fig. 8 (among Fig. 8 amplification be 300 *).Presentation graphics shown in Fig. 8 shows, CTC fluorescence (purple) skin permeation, and mainly be arranged in horny layer.
4. the tape stripping analysis of local application STAY-C50-calcium phosphate and lysozyme-calcium phosphate complex shows and is delivered in the horny layer.
The purpose of this research is the distribution of detection of active material in horny layer after local application active substance-calcium phosphate granules.
Method: estimate the distribution of STAY C50 in horny layer through the skin of having used STAY C50-calcium phosphate granules preparation is carried out serial tape stripping.Use the site on the good experimenter's forearm of labelling, apply 200 μ l preparations through scraping blade.With dry 10 minutes of said site, next carry out peeling off of ten adhesive tapes of weighing in advance then, use to be applied to the bar (3in that uses the site 2).Sonicated through in water, sample being carried out 30 minutes is extracted STAY C50 from article tape, and through the HPLC analytic sample.The article tape demonstration is delivered to cuticular the 10th (Fig. 9) with STAY-C50.
Method: estimate the distribution of lysozyme in horny layer through the skin of having used lysozyme-calcium phosphate granules preparation is carried out serial tape stripping.Use the site on the labelling human experimenter forearm, apply 200 μ l preparations through scraping blade.With dry 10 minutes of said site, next carry out peeling off of ten adhesive tapes of weighing in advance then, use to be applied to the bar (3in that uses the site 2).Through in water, sample being carried out 30 minutes supersound process from article tape, extracting lysozyme, and through the HPLC analytic sample.Detect the degree of depth (Figure 10) that lysozyme reaches 6 article tapes.
5. carry out the controlled delayed release of activating agent through the Frantz cell
Purpose: the purpose of this research is the riboflavin that detects in the riboflavin that is attached to calcium phosphate granules.
Method:
Downcut 6cm from bigger abdominal part sample 2The holostrome Corii Sus domestica of disk.Remove the fat of corium side with shears, skin is stored under-20 ℃ before using.Skin is fixed between two chambers of glass diffusion cell (Laboratory Glass Apparatus company, model #LG-1084-LPCT).This makes the exposed area of skin on the volume of 4.5ml receptor chamber is 5cm 2Diffusion cell is remained on 37 ℃.
Infiltration condition
Local application is spaced apart 8 hours and 16 hours.Cell body covers with Parafilm, and covers light with the aluminum packaging material.With 60rpm rotation accepter fluid phosphate buffered saline (PBS) (PBS).
The preparation of using
Prepare single lactofiavine phosphate-calcium phosphate granules to send 0.35-1.15mg riboflavin (20%-38% suspension).
Prepare single lactofiavine phosphate among the PBS to send 0.3-0.45mg riboflavin by 1.5mg/mL.
Use the preparation of 50-100 μ l volume with pipet.Riboflavin-calcium phosphate complex to using carries out air drying, the suction of isopyknic 0.5M sodium acetate buffer is measured use on the site then.
The matched group experiment is included in does not have the calcium phosphate granules ana to use riboflavin.
Sample collection
When skin surface still is retained in the diffuser casing it is carried out twice washing, use 1mL PBS at every turn.From diffusion cell, take out skin and carry out drying and analysis.
Sample analysis
Washing and accepter fluid: measure fluidic approximate volumes.With sample with 10,000rpm rotation 30 seconds and with calcium phosphate granules separate, dry and weigh.Remove supernatant then also with the analysis of UV spectrometer.If the UV absorbance is saturated (surpassing＞2.0), then dilute with water sample.The UV absorbance of record 370nm.
Skin: mix with the skin chopping and with the 10% trichloroacetic acid solution of 5ml.Sample carried out 1 hour supersound process with Vltrasonic device under 50 ℃.With 10, centrifugal 10 minutes of 000rpm removes supernatant also with the analysis of UV spectrometer with sample.If the UV absorbance is saturated (surpassing＞2.0), then dilute with water sample.The maximum UV absorbance of record 370nm.
The result
Owing to after 8 hours and 16 hours, in the receptor fluid, detect the existence of riboflavin metabolite, so riboflavin has all penetrated skin from aqueous solution and from the calcium phosphate granules complex.The calcium phosphate granules complex causes slower active substance to discharge.The result is shown in Figure 11 with graphics mode.
Though for the clear purpose of understanding has described aforementioned invention in greater detail by means of diagram and embodiment; But what those of ordinary skill in the art's instruction content according to the present invention may be obvious that is under the situation of essence that does not depart from accompanying claims and scope, can carry out some change and modification to it.
Therefore, preamble has only been set forth principle of the present invention.Be understood that: those skilled in the art can design variety of way, though these modes are not described clearly in this article or shown, can embody principle of the present invention, and be included in essence of the present invention and the scope.In addition; Cited all embodiment and conditionality expression way mainly are intended to help reader understanding's principle of the present invention and inventor's horn of plenty prior art and the notion that proposes among this paper, and should be interpreted as this concrete listed examples and the condition of being not limited to.In addition, among this paper all explanations of enumerating principle of the present invention, characteristics and embodiment with and concrete embodiment all be intended to comprise the equivalent on its 26S Proteasome Structure and Function.In addition, this equivalent is intended to comprise present known equivalent and the equivalent of developing in the future, and promptly any key element of the enforcement identical function of exploitation does not have and concerns its structure.Therefore, scope of the present invention is not intended to be subject to shown in this paper and the exemplary of describing.But essence of the present invention and scope are limited accompanying claims.

Claims (18)

1. compositions that comprises the spherical nanoporous calcium phosphate of even rigidity calcium phosphate granules, wherein said granule has 2 microns or littler mean diameter, and compound with activating agent.
2. compositions according to claim 1, wherein said particulate void content is in 30% to 85% scope.
3. compositions according to claim 2, wherein said particulate aperture is in the scope of 2nm to 100nm.
4. compositions according to claim 1 wherein makes said granule in the following manner:
The fluid composition of preparation calcium phosphate crystal;
By the dry said fluid composition of mode that is enough to produce precursor granules; And
Mode by being enough to produce the spherical nanoporous calcium phosphate of even rigidity calcium phosphate granules makes said precursor granules stand high temperature and high pressure.
5. compositions according to claim 4, wherein said drying comprises spray drying.
6. compositions according to claim 1, wherein said compositions is a topical formulations.
7. compositions according to claim 1 is wherein with the scope at every gram granule 0.01mg to 300mg activating agent of the compound active dose of said granule.
8. method of giving the experimenter with bioactive agent delivery, said method comprises:
Thereby the compositions that will comprise following component is used to said experimenter's regional area and is sent said activating agent to the experimenter:
The even spherical nanoporous calcium phosphate of rigidity calcium phosphate granules, wherein said granule have 2 microns or littler mean diameter and compound with activating agent.
9. method according to claim 8, wherein said particulate void content is in 30% to 85% scope.
10. method according to claim 9, wherein said particulate aperture is in the scope of 2nm to 100nm.
11. method according to claim 8 is wherein with the scope of the compound active dose of said granule at every gram granule 0.01mg to 300mg activating agent.
12. method according to claim 8, wherein said local location are the mucosa position.
13. method according to claim 8, wherein said local location are the keratinized skin surface.
14. method according to claim 13, wherein said method are that said activating agent is delivered to the method in said experimenter's the horny layer at least.
15. method according to claim 13, wherein said method are that said bioactive agent delivery is delivered to the method in said experimenter's the deep horny layer.
16. method according to claim 13, wherein said method are to pass the method that horny layer is sent said activating agent.
17. method according to claim 13, wherein said method are that said bioactive agent delivery is delivered to the method in said experimenter's the corium.
18. method according to claim 13, wherein said method are the methods to the said activating agent of said experimenter's systemic delivery.
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